Solid forms of a thienopyrimidinedione ACC inhibitor and methods for production thereof

ABSTRACT

The present invention provides solid forms of compounds useful as inhibitors of Acetyl CoA Carboxylase (ACC), compositions thereof, methods of producing the same, and methods of using the same in the treatment of ACC-mediated diseases.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit under 35 U.S.C. § 119(e) to U.S.Provisional Application No. 62/302,755, filed on Mar. 2, 2016, and U.S.Provisional Application No. 62/303,237, filed on Mar. 3, 2016, both ofwhich are incorporated herein by reference.

BACKGROUND OF THE INVENTION

Obesity is a health crisis of epic proportions. The health burden ofobesity, measured by quality-adjusted life-years lost per adult, hassurpassed that of smoking to become the most serious, preventable causeof death. In the U.S., about 34% of adults have obesity, up from 31% in1999 and about 15% in the years 1960 through 1980. Obesity increases therate of mortality from all causes for both men and women at all ages andin all racial and ethnic groups. Obesity also leads to socialstigmatization and discrimination, which decreases quality of lifedramatically. The chronic diseases that result from obesity cost theU.S. economy more than $150 billion in weight-related medical bills eachyear. Furthermore, about half of the obese population, and 25% of thegeneral population, have metabolic syndrome, a condition associated withabdominal obesity, hypertension, increased plasma triglycerides,decreased HDL cholesterol, and insulin resistance, which increases therisk for type-2 diabetes (T2DM), stroke and coronary heart disease(Harwood, Expert Opin. Ther. Targets 9: 267, 2005).

Diet and exercise, even when used in conjunction with the currentpharmacotherapy, do not provide sustainable weight loss needed forlong-term health benefit. Currently, only a few anti-obesity drugs areapproved in the U.S., the fat absorption inhibitor orlistat (Xenical®),the 5-HT2C antagonist lorcaserin (Belviq®), and the combination therapyphentermine/topiramate (Qsymia®). Unfortunately, poor efficacy andunappealing gastrointestinal side effects limit the use of orlistat.Surgery can be effective but is limited to patients with extremely highBody Mass Indices (BMI) and the low throughput of surgery limits theimpact of this modality to about 200 k patients per year. The majorityof obesity drugs in clinical development are designed to reduce caloricintake through central action in the CNS (e.g., anorectics and satietyagents). However, the FDA has taken an unfavorable position againstCNS-active agents, due to their modest efficacy and observed/potentialside-effect profiles.

The continuing and increasing problem of obesity, and the current lackof safe and effective drugs for treating it, highlight the overwhelmingneed for new drugs to treat this condition and its underlying causes.

Another ongoing problem is the lack of antifungal drugs with activityagainst a broad range of fungal pathogens. Often, a given antifungaldrug will have activity against one fungal species but lack activityagainst other, even closely related, species, such as Candida albicans,Candida krusei, and Candida parapsilosis.

SUMMARY

The compound,(R)-2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)-2-methylpropanoic acid, designated herein as Compound 1, hasthe formula:

The present disclosure relates to various crystalline forms of Compound1, processes for making Compound 1 and its various forms, and methods ofusing such forms.

Compound 1 also provides forms further described herein as “Compound 1Form I,” “Compound 1 Form II,” “Compound 1 Form III,” “Compound 1 FormIV,” “Compound 1 Form V,” “Compound 1 Form VI,” “Compound 1 Form VII,”“Compound 1 Form VIII,” and “amorphous Compound 1.”

Additional crystalline forms of Compound 1 are further described herein.

In some embodiments, crystalline forms of Compound 1 may include a salt,a co-crystal, a solvate, or a hydrate of Compound 1.

In some embodiments, crystalline forms of Compound 1 may include a saltof Compound 1. In some embodiments, Compound 1 provide forms furtherdescribed herein as “Compound 1 Sodium Form I,” “Compound 1 Sodium FormII,” “Compound 1 Calcium Form I,” “Compound 1 Magnesium Form I,”“Compound 1 Diethanolamine Form I,” and “Compound 1 Piperazine Form I.”

Some embodiments provide for a process of preparing Compound 1, or asalt or co-crystal thereof, comprising:

-   (a) contacting compound G-2-a:

with oxazole under condition sufficient to form compound G-9-a:

-   (b) contacting compound G-9-a with compound (R)-G-1-a:

under conditions sufficient to form a compound G-4-a:

and

-   (c) hydrolyzing compound G-4-a under conditions sufficient to form    Compound 1.

Some embodiments provide for a process of preparing Compound 1, or saltor co-crystal thereof, comprising:

-   (a) contacting compound (R)-G-5-a or an oxygen anion thereof:

with a sulfonylating reagent under conditions sufficient to formcompound (R)-G-6-a:

-   (b) contacting compound (R)-G-6-a with a bromide salt under    conditions sufficient to form compound (R)-G-1-a:

-   (c) contacting compound G-2-a:

with oxazole under conditions sufficient to form compound G-9-a:

-   (d) contacting compound G-9-a with compound (R)-G-1-a under    conditions sufficient to form a compound G-4-a:

-   and (e) hydrolyzing compound G-4-a under conditions sufficient to    form Compound 1.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A depicts a X-Ray powder diffraction (XRPD) pattern of Form I ofCompound 1.

FIG. 1B depicts another X-Ray powder diffraction (XRPD) pattern of FormI of Compound 1.

FIG. 2 depicts the ellipsoid diagram of Form I of Compound 1.

FIG. 3A depicts a differential scanning calorimeter (DSC) curve of FormI of Compound 1.

FIG. 3B depicts another differential scanning calorimeter (DSC) curve ofForm I of Compound 1.

FIG. 4A depicts a thermogravimetric analysis (TGA) of Form I of Compound1.

FIG. 4B depicts another thermogravimetric analysis (TGA) of Form I ofCompound 1.

FIG. 5 depicts the X-Ray powder diffraction pattern of Form II ofCompound 1.

FIG. 6 depicts the X-Ray powder diffraction pattern of Form III ofCompound 1.

FIG. 7A depicts a X-Ray powder diffraction pattern of Form IV ofCompound 1.

FIG. 7B depicts another X-Ray powder diffraction pattern of Form IV ofCompound 1.

FIG. 8 depicts the differential scanning calorimeter (DSC) curve of FormIV of Compound 1.

FIG. 9 depicts the thermogravimetric analysis (TGA) of Form IV ofCompound 1.

FIG. 10 depicts the X-Ray powder diffraction pattern of Form V ofCompound 1.

FIG. 11A depicts a X-Ray powder diffraction pattern of Form VI ofCompound 1.

FIG. 11B depicts another X-Ray powder diffraction pattern of Form VI ofCompound 1.

FIG. 12 depicts the differential scanning calorimeter (DSC) curve ofForm VI of Compound 1.

FIG. 13 depicts the thermogravimetric analysis (TGA) of Form VI ofCompound 1.

FIG. 14 depicts the X-Ray powder diffraction pattern of Form VII ofCompound 1.

FIG. 15A depicts a X-Ray powder diffraction pattern of Form VIII ofCompound 1.

FIG. 15B depicts another X-Ray powder diffraction pattern of Form VIIIof Compound 1.

FIG. 16 depicts the differential scanning calorimeter (DSC) curve ofForm VIII of Compound 1.

FIG. 17 depicts the thermogravimetric analysis (TGA) of Form VIII ofCompound 1.

FIG. 18 depicts the X-Ray powder diffraction pattern of amorphousCompound 1.

FIG. 19 depicts the X-Ray powder diffraction pattern of Compound 1Sodium Form I.

FIG. 20 depicts the differential scanning calorimeter (DSC) curve ofCompound 1 Sodium Form I.

FIG. 21 depicts the thermogravimetric analysis (TGA) of Compound 1Sodium Form I.

FIG. 22 depicts the X-Ray powder diffraction pattern of Compound 1Sodium Form II.

FIG. 23 depicts the differential scanning calorimeter (DSC) curve ofCompound 1 Sodium Form II.

FIG. 24 depicts the thermogravimetric analysis (TGA) of Compound 1Sodium Form II.

FIG. 25 depicts the X-Ray powder diffraction pattern of Compound 1Calcium Form I.

FIG. 26 depicts the differential scanning calorimeter (DSC) curve ofCompound 1 Calcium Form I.

FIG. 27 depicts the thermogravimetric analysis (TGA) of Compound 1Calcium Form I.

FIG. 28 depicts the X-Ray powder diffraction pattern of Compound 1Magnesium Form I.

FIG. 29 depicts the differential scanning calorimeter (DSC) curve ofCompound 1 Magnesium Form I.

FIG. 30 depicts the thermogravimetric analysis (TGA) of Compound 1Magnesium Form I.

FIG. 31 depicts the X-Ray powder diffraction pattern of Compound 1Diethanolamine Form I.

FIG. 32 depicts the differential scanning calorimeter (DSC) curve ofCompound 1 Diethanolamine Form I.

FIG. 33 depicts the thermogravimetric analysis (TGA) of Compound 1Diethanolamine Form I.

FIG. 34 depicts the X-Ray powder diffraction pattern of Compound 1Piperazine Form I.

FIG. 35 depicts the differential scanning calorimeter (DSC) curve ofCompound 1 Piperazine Form I.

FIG. 36 depicts the thermogravimetric analysis (TGA) of Compound 1Piperazine Form I.

FIG. 37 depicts the differential scanning calorimeter (DSC) curve ofForm II of Compound 1.

FIG. 38 depicts the differential scanning calorimeter (DSC) curve ofForm III of Compound 1.

FIG. 39 depicts the differential scanning calorimeter (DSC) curve ofForm V of Compound 1.

FIG. 40 depicts the differential scanning calorimeter (DSC) curve ofForm VII of Compound 1.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

1. General Description

United States Published Patent Application Number 2013/0123231 A1,published May 16, 2013, and incorporated herein by reference in itsentirety, discloses certain thienopyrimidinedione compounds that bind toand inhibit Acetyl CoA Carboxylases 1 and 2. Such compounds includeCompound 1:

Compound 1,((R)-2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)-2-methylpropanoic acid), is designated as compound number1-181, and the synthesis of Compound 1 is described in detail at Example76 of U.S. Patent Publication 2013/0123231.

Compound 1 is active in a variety of assays and therapeutic models,including those demonstrating inhibition of ACC1 and/or ACC2, inhibitionof fatty acid synthesis, and stimulation of fatty acid oxidation. Itwould be desirable to provide solid forms of Compound 1 that impartcharacteristics such as improved aqueous solubility, stability, and easeof formulation.

Also disclosed are novel synthetic methods for producing Compound 1 andanalogs thereof, as well as novel intermediates in the synthesis of suchcompounds. Such methods and intermediates are amenable to large scaleproduction, owing to high yields, favorable physicochemical properties,and reduced use of toxic reagents or solvents compared to the state ofthe art.

2. Solid Forms of Compound 1

In some embodiments, the present invention provides a solid form ofCompound 1, or a salt, co-crystal, solvate, or hydrate thereof. In someembodiments, the solid form of Compound 1 is a salt or co-crystal. Insome embodiments, the salt or co-crystal is a pharmaceuticallyacceptable salt or co-crystal thereof. In some embodiments, the presentinvention provides a solid form of Compound 1, or a pharmaceuticallyacceptable salt thereof. In some embodiments, the present inventionprovides a solid form of Compound 1, or a pharmaceutically acceptableco-crystal thereof. In some embodiments, the present invention providesa solid form of Compound 1, or a pharmaceutically acceptable saltthereof, that is substantially free of impurities. As used herein, theterm “substantially free of impurities” means that the compound containsno significant amount of extraneous matter. Such extraneous matter mayinclude residual solvents, or any other impurities that may result fromthe preparation of, and/or isolation of, Compound 1. In certainembodiments, at least about 95% by weight of Compound 1 is present. Instill other embodiments of the invention, at least about 99% by weightof Compound 1 is present. In certain embodiments, at least about 95% byweight of Compound 1, as a salt or co-crystal thereof, is present. Instill other embodiments of the invention, at least about 99% by weightof Compound 1, as a salt or co-crystal thereof is present.

According to one embodiment, Compound 1 is present in an amount of atleast about 97.0, 97.5, 98.0, 98.5, 99.0, 99.5, or 99.8 weight percentwhere the percentages are based on the total weight of the composition.According to another embodiment, Compound 1 contains no more that about3.0 area percent HPLC of total organic impurities and, in certainembodiments, no more that about 1.5 area percent HPLC total organicimpurities relative to the total area of the HPLC chromatogram. In otherembodiments, Compound 1 contains no more than about 1.0% area percentHPLC of any single impurity, and, in certain embodiments, no more thanabout 0.5 area percent HPLC of any single impurity, relative to thetotal area of the HPLC chromatogram.

In some embodiments, Compound 1 is present in an enantiomeric excess(e.e.) of about 90.0 to 99.95 percent. In some embodiments, Compound 1is present in an enantiomeric excess (e.e.) of at least about 90.0,91.0, 92.0, 93.0, 94.0, 95.0, 96.0, 97.0, 97.5, 98.0, 98.5, 99.0, 99.5,99.7, 99.8, 99.9, or 99.95 percent. In some embodiments, Compound 1 isoptically pure, and substantially free of its (S)-enantiomer.

In some embodiments, Compound 1 is present as a free acid. In someembodiments, Compound 1 is present as a salt. In some embodiments,Compound 1 is present as a pharmaceutically acceptable salt. In someembodiments, Compound 1 is present as a co-crystal.

In some embodiments, Compound 1 is an amorphous form of a salt or aco-crystal of Compound 1.

In some embodiments, Compound 1 is a crystalline form of a salt or aco-crystal of Compound 1. In some embodiments, the crystalline form of asalt or co-crystal of Compound I is: Compound 1 Sodium Form I, Compound1 Sodium Form II, Compound 1 Calcium Form I, Compound 1 Magnesium FormI, Compound 1 Diethanolamine Form I, or Compound 1 Piperazine Form I.

The structure depicted for Compound 1 is also meant to include alltautomeric forms of Compound 1. Additionally structures depicted hereare also meant to include compounds that differ only in the presence ofone or more isotopically enriched atoms. For example, compounds havingthe present structure except for the replacement of hydrogen bydeuterium or tritium, or the replacement of a carbon by a ¹³C- or¹⁴C-enriched carbon are within the scope of this invention.

It has been found that Compound 1 can exist in a variety of solid forms.Such forms include polymorphs, solvates, hydrates, and amorphous. Allsuch forms are contemplated by the present invention. In certainembodiments, the present invention provides Compound 1 as a mixture ofone or more solid forms selected from polymorphs, solvates, hydrates,and amorphous Compound 1.

In some embodiments, Compound 1 is an amorphous solid. FIG. 18 depictsthe X-Ray powder diffraction pattern of amorphous Compound 1. In certainembodiments, the present invention provides Compound 1 as an amorphoussolid substantially free of crystalline Compound 1. As used herein, theterm “substantially free of crystalline Compound 1” means that thecompound contains no significant amount of crystalline Compound 1. Incertain embodiments, at least about 95% by weight of amorphous Compound1 is present. In still other embodiments, of the invention, at leastabout 99% by weight of amorphous Compound 1 is present.

As used herein, the term “polymorph” refers to any of the differentcrystal structures in which a compound can crystallize. As used herein,the term “solvate” refers to a crystal form with either a stoichiometricor non-stoichiometric amount of solvent incorporated into the crystalstructure. Similarly, the term “hydrate” refers specifically to acrystal form with either a stoichiometric or non-stoichiometric amountof water incorporated into the crystal structure.

In certain embodiments, Compound 1 is a crystalline solid. In someembodiments, Compound 1 is a crystalline solid substantially free ofamorphous Compound 1. As used herein, the term “substantially free ofamorphous Compound 1” means that the compound contains no significantamount of amorphous Compound 1. In certain embodiments, at least about95% by weight of crystalline Compound 1 is present. In still otherembodiments, of the invention, at least about 99% by weight ofcrystalline Compound 1 is present.

In some embodiments, Compound 1 is substantially free of any water orother solvent. In some embodiments, Compound 1 is a neat crystal form,and thus does not have any water or other solvent incorporated into itscrystal structure. It has now been found that Compound 1 can exist in atleast one distinct neat (i.e. anhydrous, non-solvate) crystal form. Suchneat crystal forms of Compound 1 include Form I, Form VII, and FormVIII, each of which is described in detail herein.

In some embodiments, the present invention provides a solvatedcrystalline form of Compound 1. Such solvated crystalline forms ofCompound 1 include Form II (DMF solvate), Form III (DMSO solvate), FormIV (methanol solvate), Form V (NMP solvate), and Form VI (toluenesolvate).

In some embodiments, the present invention provides a crystalline formof Compound 1 selected from any of those referred to as Form I, Form II,Form III, Form IV, Form V, Form VI, Form VII, or Form VIII. Methods forpreparing each of Forms I through VIII of Compound 1 are describedherein.

In some embodiments, the present invention provides a polymorphic formof Compound 1 referred to as Form I.

In some embodiments, the present invention provides Form I of Compound1, having a powder X-ray diffraction pattern substantially similar tothat depicted in FIG. 1A.

As used herein, the term “about,” when used in reference to a degree 2θvalue refers to the stated value+0.1 degree 2θ, obtained under thesample preparation and data collection conditions described in theexemplification. In some embodiments, the term “about,” when used inreference to a degree 2θ value refers to the stated value+0.2 degree 2θ.One of skill in the art will appreciate that changes in the particularXRPD acquisition parameters will affect the XRPD pattern and specificvalues of degrees 2θ obtained.

In some embodiments, Form I of Compound 1 is characterized in that ithas one or more peaks in its powder X-ray diffraction pattern selectedfrom those in Table 1 below.

TABLE 1 Compound 1 Form I XRPD Peaks Relative Position (°2θ) Height(cts) Intensity (%) 8.73 1552 6.83 9.23 22736 100 12.13 1828 8.04 12.281818 8.00 12.51 609 2.68 13.74 1245 5.48 14.74 2776 12.21 14.89 314313.82 15.83 1881 8.27 15.92 1400 6.16 17.19 2164 9.52 17.87 1294 5.6918.32 1466 6.45 18.44 1556 6.84 19.11 1171 5.15 19.29 621 2.74 19.602289 10.07 19.91 359 1.58 20.74 561 2.47 21.04 528 2.32 22.49 919 4.0423.85 964 4.24 23.96 1534 6.75 25.58 1762 7.75 27.00 541 2.38 27.29 9574.21 28.17 454 2.00 28.58 512 2.26 28.92 339 1.49 35.54 242 1.06 38.91131 0.58

In some embodiments, Form I of Compound 1 is characterized in that ithas two or more peaks in its powder X-ray diffraction pattern selectedfrom those in Table 1. In some embodiments, Form I of Compound 1 ischaracterized in that it has three or more peaks in its powder X-raydiffraction pattern selected from those in Table 1. In some embodiments,Form I of Compound 1 is characterized in that it has four or more peaksin its powder X-ray diffraction pattern selected from those in Table 1.In some embodiments, Form I of Compound 1 is characterized in that ithas five or more peaks in its powder X-ray diffraction pattern selectedfrom those in Table 1. In some embodiments, Form I of Compound 1 ischaracterized in that it has ten of the peaks in Table 1 in its X-raydiffraction pattern. In some embodiments, Form I of Compound 1 ischaracterized in that it has fifteen of the peaks in Table 1 in itsX-ray diffraction pattern. In some embodiments, Form I of Compound 1 ischaracterized in that it has twenty of the peaks in Table 1 in its X-raydiffraction pattern. In some embodiments, Form I of Compound 1 ischaracterized in that it has all of the peaks in Table 1 in its X-raydiffraction pattern.

In some embodiments, Form I of Compound 1 is characterized in that ithas one or more peaks in its powder X-ray diffraction pattern selectedfrom those at about 12.51, about 14.89, about 17.19, about 19.11, about19.91, about 28.58, and about 38.91 degrees 2θ. In some embodiments,Form I of Compound 1 is characterized in that it has two or more peaksin its powder X-ray diffraction pattern selected from those at about12.51, about 14.89, about 17.19, about 19.11, about 19.91, about 28.58,and about 38.91 degrees 2θ. In some embodiments, Form I of Compound 1 ischaracterized in that it has three or more peaks in its powder X-raydiffraction pattern selected from those at about 12.51, about 14.89,about 17.19, about 19.11, about 19.91, about 28.58, and about 38.91degrees 2θ. In some embodiments, Form I of Compound 1 is characterizedin that it has four or more peaks in its powder X-ray diffractionpattern selected from those at about 12.51, about 14.89, about 17.19,about 19.11, about 19.91, about 28.58, and about 38.91 degrees 2θ. Insome embodiments, Form I of Compound 1 is characterized in that it hasfive or more peaks in its powder X-ray diffraction pattern selected fromthose at about 12.51, about 14.89, about 17.19, about 19.11, about19.91, about 28.58, and about 38.91 degrees 2θ. In some embodiments,Form I of Compound 1 is characterized in that it has six or more peaksin its powder X-ray diffraction pattern selected from those at about12.51, about 14.89, about 17.19, about 19.11, about 19.91, about 28.58,and about 38.91 degrees 2θ. In some embodiments, Form I of Compound 1 ischaracterized in that it has all seven peaks in its powder X-raydiffraction pattern selected from those at about 12.51, about 14.89,about 17.19, about 19.11, about 19.91, about 28.58, and about 38.91degrees 2θ.

In some embodiments, Form I of Compound 1 is characterized in that ithas one or more peaks in its powder X-ray diffraction pattern selectedfrom those at about 9.2, about 15.8, about 19.6, about 24.0, about 25.6,about 28.6, and about 8.7 degrees 2θ. In some embodiments, Form I ofCompound 1 is characterized in that it has two or more peaks in itspowder X-ray diffraction pattern selected from those at about 9.2, about15.8, about 19.6, about 24.0, about 25.6, about 28.6, and about 8.7degrees 2θ. In some embodiments, Form I of Compound 1 is characterizedin that it has three or more peaks in its powder X-ray diffractionpattern selected from those at about 9.2, about 15.8, about 19.6, about24.0, about 25.6, about 28.6, and about 8.7 degrees 2θ. In someembodiments, Form I of Compound 1 is characterized in that it has fouror more peaks in its powder X-ray diffraction pattern selected fromthose at about 9.2, about 15.8, about 19.6, about 24.0, about 25.6,about 28.6, and about 8.7 degrees 2θ. In some embodiments, Form I ofCompound 1 is characterized in that it has five or more peaks in itspowder X-ray diffraction pattern selected from those at about 9.2, about15.8, about 19.6, about 24.0, about 25.6, about 28.6, and about 8.7degrees 2θ. In some embodiments, Form I of Compound 1 is characterizedin that it has six or more peaks in its powder X-ray diffraction patternselected from those at about 9.2, about 15.8, about 19.6, about 24.0,about 25.6, about 28.6, and about 8.7 degrees 2θ. In some embodiments,Form I of Compound 1 is characterized by an X-ray diffraction patterncomprising the following peaks: about 9.2, about 15.8, about 19.6, about24.0, about 25.6, about 28.6, and about 8.7 degrees 2θ.

In some embodiments, Form I is characterized by an X-ray powderdiffractogram comprising the following peaks: 9.3, 15.0, and 19.8°2θ±0.2° 2θ, as determined on a diffractometer using Cu—Kα radiation at awavelength of 1.54 Å. In some embodiments, the diffractogram comprisesadditional peaks at 16.0, 24.0, 25.8, and 27.3° 2θ±0.2° 2θ. Compound 1Form I is also characterized by its X-ray diffraction pattern assubstantially shown in FIG. 1A. Compound 1 Form I is also characterizedby its X-ray diffraction pattern as substantially shown in FIG. 1B.

Form I of Compound 1 has been characterized via single crystal analysisand the data are summarized in Table 2 and the ellipsoid diagram isshown in FIG. 2.

TABLE 2 Crystal Data and Data Collection Parameters Empirical formulaC₂₈H₃₁N₃O₈S Formula weight (g mol−1) 569.62 Temperature (K) 293(2)Wavelength (Å) 1.54184 Crystal system orthorhombic Space group C2221Unit cell parameters a = 14.77743(18) Å α = 90° b = 14.62619(16) Å β =90° c = 51.7778(8) Å γ = 90° Unit cell volume (Å3) 11191.1(3) Cellformula units, Z 16 Calculated density (g cm−3) 1.352 Absorptioncoefficient (mm−1) 1.495 F(000) 4800 Crystal size (mm3) 0.19 × 0.13 ×0.06 Reflections used for cell 15725 measurement θ range for cellmeasurement 3.5010°-77.2150° Total reflections collected 29754 Indexranges −18 ≤ h ≤ 18; −14 ≤ k ≤ 18; −63≤/≤58 θ range for data collectionθmin = 3.414°, θmax = 77.642° Completeness to θmax 98.2% Completeness toθfull = 67.684° 99.7% Absorption correction multi-scan Transmissioncoefficient range 0.918-1.000 Refinement method full matrixleast-squares on Fsqd Independent reflections 11199 [Rint = 0.0330, Rσ =0.0361] Reflections [I > 2σ(I)] 9830 Reflections/restraints/parameters11199/0/737 Goodness-of-fit on F2 S = 1.05 Final residuals [I > 2σ(I)] R= 0.0446, Rw = 0.1187 Final residuals [all reflections] R = 0.0516, Rw =0.1250 Largest diff. peak and hole (e Å−3) 0.405, −0.297 Max/meanshift/standard 0.001/0.000 uncertainty Absolute Structure DeterminationFlack parameter: −0.007(8) Hooft parameter: −0.011(7) Friedel coverage:88.7%

In some embodiments, Form I of Compound 1 is characterized by adifferential scanning calorimetry (DSC) curve that comprises anendotherm between about 189° C. to about 193° C. Form I of Compound 1 isalso characterized by its DSC curve as substantially shown in FIG. 3A.In some embodiments, Form I of Compound 1 is also characterized by itsDSC curve as substantially shown in FIG. 3B.

In some embodiments, Form I of Compound 1 is characterized by athermogravimetric analysis (TGA) curve as substantially shown in FIG.4A. In some embodiments, Form I of Compound 1 is characterized by athermogravimetric analysis (TGA) curve as substantially shown in FIG.4B.

In some embodiments, at least about 95% by weight of Form I of Compound1 is present. In some embodiments, at least about 99% by weight of FormI of Compound 1 is present.

In some embodiments, the crystalline form is at least about 85% of FormI. In some embodiments, the crystalline form is at least about 90% ofForm I. In some embodiments, the crystalline form is at least about 95%of Form I. In some embodiments, the crystalline form is at least about99% of Form I. In some embodiments, the crystalline form is at leastabout 99.5% of Form I. In some embodiments, the crystalline form is atleast about 99.9% of Form I. In some embodiments, the crystalline formis at least about 99.99% of Form I.

Some embodiments provide for a pharmaceutical composition comprisingCompound 1 in Form I. In one embodiment, the pharmaceutical compositioncomprises Compound 1 wherein at least about 85% of Compound 1 is in FormI. In one embodiment, the pharmaceutical composition comprises Compound1 wherein at least about 90% of Compound 1 is in Form I. In oneembodiment, the pharmaceutical composition comprises Compound 1 whereinat least about 95% of Compound 1 is in Form I. In one embodiment, thepharmaceutical composition comprises Compound 1 wherein at least about99% of Compound 1 is in Form I. In one embodiment, the pharmaceuticalcomposition comprises Compound 1 wherein at least about 99.5% ofCompound 1 is in Form I. In one embodiment, the pharmaceuticalcomposition comprises Compound 1 wherein at least about 99.9% ofCompound 1 is in Form I. In one embodiment, the pharmaceuticalcomposition comprises Compound 1 wherein at least about 99.99% ofCompound 1 is in Form I.

In some embodiments, the present invention provides a solvatedcrystalline form of Compound 1 referred to as Form II. In someembodiments, the present invention provides Form II of Compound 1,having a powder X-ray diffraction pattern substantially similar to thatdepicted in FIG. 5. In some embodiments, Form II of Compound 1 ischaracterized in that it has one or more peaks in its powder X-raydiffraction pattern selected from those in Table 3 below.

TABLE 3 Compound 1 Form II XRPD Peaks Relative Position (°2θ) Height(cts) Intensity (%) 7.56 124.9 57.7 8.09 137.8 63.7 9.18 77.0 35.6 11.3434.6 16.0 11.74 75.6 35.0 12.21 51.9 24.0 12.80 35.1 16.2 14.37 31.614.6 15.38 96.4 44.6 15.80 28.8 13.3 17.01 50.8 23.5 17.56 30.2 14.018.30 20.3 9.4 19.56 216.3 100.0 20.67 28.6 13.2 21.00 50.3 23.2 22.77128.2 59.3 23.00 44.7 20.7 23.29 73.6 34.0 25.62 159.8 73.9 26.23 14.26.6 27.05 30.4 14.0 28.92 31.5 14.6

In some embodiments, Form II of Compound 1 is characterized in that ithas two or more peaks in its powder X-ray diffraction pattern selectedfrom those in Table 3. In some embodiments, Form II of Compound 1 ischaracterized in that it has three or more peaks in its powder X-raydiffraction pattern selected from those in Table 3. In some embodiments,Form II of Compound 1 is characterized in that it has four or more peaksin its powder X-ray diffraction pattern selected from those in Table 3.In some embodiments, Form II of Compound 1 is characterized in that ithas five or more peaks in its powder X-ray diffraction pattern selectedfrom those in Table 3. In some embodiments, Form II of Compound 1 ischaracterized in that it has all of the peaks in Table 3 in its X-raydiffraction pattern.

In some embodiments, Form II of Compound 1 is characterized in that ithas one or more peaks in its powder X-ray diffraction pattern selectedfrom those at about 7.56, about 8.09, about 11.34, about 11.74, about14.37, about 15.38, about 17.56, and about 23.00 degrees 2θ. In someembodiments, Form II of Compound 1 is characterized in that it has twoor more peaks in its powder X-ray diffraction pattern selected fromthose at about 7.56, about 8.09, about 11.34, about 11.74, about 14.37,about 15.38, about 17.56, and about 23.00 degrees 2θ. In someembodiments, Form II of Compound 1 is characterized in that it has threeor more peaks in its powder X-ray diffraction pattern selected fromthose at about 7.56, about 8.09, about 11.34, about 11.74, about 14.37,about 15.38, about 17.56, and about 23.00 degrees 2θ. In someembodiments, Form II of Compound 1 is characterized in that it has fouror more peaks in its powder X-ray diffraction pattern selected fromthose at about 7.56, about 8.09, about 11.34, about 11.74, about 14.37,about 15.38, about 17.56, and about 23.00 degrees 2θ. In someembodiments, Form II of Compound 1 is characterized in that it has fiveor more peaks in its powder X-ray diffraction pattern selected fromthose at about 7.56, about 8.09, about 11.34, about 11.74, about 14.37,about 15.38, about 17.56, and about 23.00 degrees 2θ. In someembodiments, Form II of Compound 1 is characterized in that it has sixor more peaks in its powder X-ray diffraction pattern selected fromthose at about 7.56, about 8.09, about 11.34, about 11.74, about 14.37,about 15.38, about 17.56, and about 23.00 degrees 2θ. In someembodiments, Form II of Compound 1 is characterized in that it has sevenor more peaks in its powder X-ray diffraction pattern selected fromthose at about 7.56, about 8.09, about 11.34, about 11.74, about 14.37,about 15.38, about 17.56, and about 23.00 degrees 2θ. In someembodiments, Form II of Compound 1 is characterized in that it has alleight peaks in its powder X-ray diffraction pattern selected from thoseat about 7.56, about 8.09, about 11.34, about 11.74, about 14.37, about15.38, about 17.56, and about 23.00 degrees 2θ.

In some embodiments, Form II of Compound 1 is characterized in that ithas one or more peaks in its powder X-ray diffraction pattern selectedfrom those at about 12.2, about 12.8, about 17.0, about 19.6, about21.0, and about 22.8 degrees 2θ.

In some embodiments, the present invention provides a solvatedcrystalline form of Compound 1 referred to as Form III. In someembodiments, the present invention provides Form III of Compound 1,having a powder X-ray diffraction pattern substantially similar to thatdepicted in FIG. 6. In some embodiments, Form III of Compound 1 ischaracterized in that it has one or more peaks in its powder X-raydiffraction pattern selected from those in Table 4 below.

TABLE 4 Compound 1 Form III XRPD Peaks Relative Position (°2θ) Height(cts) Intensity (%) 6.27 38.8 27.5 7.95 51.2 20.5 8.10 67.3 26.9 8.50153.5 61.4 9.16 21.4 8.6 12.18 250.2 100.0 15.76 114.7 45.8 15.88 227.190.8 17.89 18.7 7.5 18.02 38.7 15.5 21.61 61.2 24.5 23.27 42.9 17.123.78 39.1 15.6 24.14 41.3 16.5 26.00 33.3 13.3 26.21 28.0 11.2

In some embodiments, Form III of Compound 1 is characterized in that ithas two or more peaks in its powder X-ray diffraction pattern selectedfrom those in Table 4. In some embodiments, Form III of Compound 1 ischaracterized in that it has three or more peaks in its powder X-raydiffraction pattern selected from those in Table 4. In some embodiments,Form III of Compound 1 is characterized in that it has four or morepeaks in its powder X-ray diffraction pattern selected from those inTable 4. In some embodiments, Form III of Compound 1 is characterized inthat it has five or more peaks in its powder X-ray diffraction patternselected from those in Table 4. In some embodiments, Form III ofCompound 1 is characterized in that it has all of the peaks in Table 4in its X-ray diffraction pattern.

In some embodiments, Form III of Compound 1 is characterized in that ithas one or more peaks in its powder X-ray diffraction pattern selectedfrom those at about 6.27, about 18.02, about 21.61, and about 24.14degrees 2θ. In some embodiments, Form III of Compound 1 is characterizedin that it has two or more peaks in its powder X-ray diffraction patternselected from those at about 6.27, about 18.02, about 21.61, and about24.14 degrees 2θ. In some embodiments, Form III of Compound 1 ischaracterized in that it has three or more peaks in its powder X-raydiffraction pattern selected from those at about 6.27, about 18.02,about 21.61, and about 24.14 degrees 2θ. In some embodiments, Form IIIof Compound 1 is characterized in that it has all four peaks in itspowder X-ray diffraction pattern selected from those at about 6.27,about 18.02, about 21.61, and about 24.14 degrees 2θ.

In some embodiments, Form III of Compound 1 is characterized in that ithas one or more peaks in its powder X-ray diffraction pattern selectedfrom those at about 6.3, about 8.5, about 12.2, about 15.9, and about21.6 degrees 2θ.

In some embodiments, the present invention provides a solvatedcrystalline form of Compound 1 referred to as Form IV. In someembodiments, the present invention provides Form IV of Compound 1,having a powder X-ray diffraction pattern substantially similar to thatdepicted in FIG. 7A. In some embodiments, the present invention providesForm IV of Compound 1, having a powder X-ray diffraction patternsubstantially similar to that depicted in FIG. 7B. In some embodiments,Form IV of Compound 1 is characterized in that it has one or more peaksin its powder X-ray diffraction pattern selected from those listed inTable 5 below.

TABLE 5 Compound 1 Form IV XRPD Peaks Relative Position (°2θ) Height(cts) Intensity (%) 8.60 18.2 4.2 8.73 19.6 4.5 9.73 147.8 34.0 9.88435.1 100 10.56 183.9 42.3 10.70 127.6 29.3 11.86 107.8 24.8 11.97 58.213.4 13.50 139.5 32.1 14.54 126.5 29.1 15.80 29.7 6.8 16.46 19.2 4.416.62 41.5 9.5 17.74 46.1 10.6 19.30 120.7 27.7 20.36 253.3 58.2 21.3024.6 5.7 21.94 385.6 88.6 23.90 30.7 7.1 25.61 55.5 12.8 26.72 405.393.2 28.28 41.3 9.5 29.02 43.2 9.9

In some embodiments, Form IV of Compound 1 is characterized in that ithas two or more peaks in its powder X-ray diffraction pattern selectedfrom those in Table 5. In some embodiments, Form IV of Compound 1 ischaracterized in that it has three or more peaks in its powder X-raydiffraction pattern selected from those in Table 5. In some embodiments,Form IV of Compound 1 is characterized in that it has four or more peaksin its powder X-ray diffraction pattern selected from those in Table 5.In some embodiments, Form IV of Compound 1 is characterized in that ithas five or more peaks in its powder X-ray diffraction pattern selectedfrom those in Table 5. In some embodiments, Form IV of Compound 1 ischaracterized in that it has all of the peaks in Table 5 in its X-raydiffraction pattern.

In some embodiments, Form IV of Compound 1 is characterized in that ithas one or more peaks in its powder X-ray diffraction pattern selectedfrom those at about 9.73, about 9.88, about 10.56, about 10.70, about11.86, about 11.97, about 14.54, about 16.62, about 21.30, about 21.94,and about 26.72 degrees 2θ. In some embodiments, Form IV of Compound 1is characterized in that it has two or more peaks in its powder X-raydiffraction pattern selected from those at about 9.73, about 9.88, about10.56, about 10.70, about 11.86, about 11.97, about 14.54, about 16.62,about 21.30, about 21.94, and about 26.72 degrees 2θ. In someembodiments, Form IV of Compound 1 is characterized in that it has threeor more peaks in its powder X-ray diffraction pattern selected fromthose at about 9.73, about 9.88, about 10.56, about 10.70, about 11.86,about 11.97, about 14.54, about 16.62, about 21.30, about 21.94, andabout 26.72 degrees 2θ. In some embodiments, Form IV of Compound 1 ischaracterized in that it has four or more peaks in its powder X-raydiffraction pattern selected from those at about 9.73, about 9.88, about10.56, about 10.70, about 11.86, about 11.97, about 14.54, about 16.62,about 21.30, about 21.94, and about 26.72 degrees 2θ. In someembodiments, Form IV of Compound 1 is characterized in that it has fiveor more peaks in its powder X-ray diffraction pattern selected fromthose at about 9.73, about 9.88, about 10.56, about 10.70, about 11.86,about 11.97, about 14.54, about 16.62, about 21.30, about 21.94, andabout 26.72 degrees 2θ. In some embodiments, Form IV of Compound 1 ischaracterized in that it has six or more peaks in its powder X-raydiffraction pattern selected from those at about 9.73, about 9.88, about10.56, about 10.70, about 11.86, about 11.97, about 14.54, about 16.62,about 21.30, about 21.94, and about 26.72 degrees 2θ. In someembodiments, Form IV of Compound 1 is characterized in that it has sevenor more peaks in its powder X-ray diffraction pattern selected fromthose at about 9.73, about 9.88, about 10.56, about 10.70, about 11.86,about 11.97, about 14.54, about 16.62, about 21.30, about 21.94, andabout 26.72 degrees 2θ. In some embodiments, Form IV of Compound 1 ischaracterized in that it has nine or more peaks in its powder X-raydiffraction pattern selected from those at about 9.73, about 9.88, about10.56, about 10.70, about 11.86, about 11.97, about 14.54, about 16.62,about 21.30, about 21.94, and about 26.72 degrees 2θ. In someembodiments, Form IV of Compound 1 is characterized in that it has tenor more peaks in its powder X-ray diffraction pattern selected fromthose at about 9.73, about 9.88, about 10.56, about 10.70, about 11.86,about 11.97, about 14.54, about 16.62, about 21.30, about 21.94, andabout 26.72 degrees 2θ. In some embodiments, Form IV of Compound 1 ischaracterized in that it has all eleven peaks in its powder X-raydiffraction pattern selected from those at about 9.73, about 9.88, about10.56, about 10.70, about 11.86, about 11.97, about 14.54, about 16.62,about 21.30, about 21.94, and about 26.72 degrees 2θ.

In some embodiments, Form IV of Compound 1 is characterized in that ithas one or more peaks in its powder X-ray diffraction pattern selectedfrom those at about 9.9, about 10.6, about 11.9, about 14.5, about 16.6,about 21.9, and about 26.7 degrees 2θ.

In some embodiments, Form IV of Compound 1 is characterized by an X-raypowder diffractogram comprising the following peaks: 9.9, 10.7, 19.5,22.0, and 26.8° 2θ±0.2° 2θ, as determined on a diffractometer usingCu—Kα radiation at a wavelength of 1.54 Å. The diffractogram comprisesadditional peaks at 8.7, 12.0, and 14.7° 2θ±0.2° 2θ. Compound 1 Form IVis also characterized by its X-ray diffraction pattern as substantiallyshown in FIG. 7A. Compound 1 Form IV is also characterized by its X-raydiffraction pattern as substantially shown in FIG. 7B.

In some embodiments, Form IV of Compound 1 is characterized by adifferential scanning calorimetry (DSC) curve that comprises anendotherms at 85 and 190 and 202° C. and exotherm at 146° C. Form IV ofCompound 1 is also characterized by its DSC curve as substantially shownin FIG. 8.

In some embodiments, Form IV of Compound 1 is characterized by athermogravimetric analysis (TGA) curve as substantially shown in FIG. 9.

In some embodiments, the present invention provides a solvatedcrystalline form of Compound 1 referred to as Form V. In someembodiments, the present invention provides Form V of Compound 1, havinga powder X-ray diffraction pattern substantially similar to thatdepicted in FIG. 10. In some embodiments, Form V of Compound 1 ischaracterized in that it has one or more peaks in its powder X-raydiffraction pattern selected from those in Table 6 below.

TABLE 6 Compound 1 Form V XRPD Peaks Relative Position (°2θ) Height(cts) Intensity (%) 5.85 16.3 9 8.03 98.6 52 8.23 70.0 37 11.02 47.7 2511.15 24.2 13 12.69 104.3 55 13.34 85.9 45 13.50 77.2 41 15.68 22.3 1216.23 75.1 40 16.28 37.2 20 16.51 92.8 49 17.32 14.6 8 17.87 24.0 1318.93 26.0 14 20.29 47.2 25 20.69 69.6 37 22.66 189.4 100 23.47 45.9 2424.56 27.3 14 25.40 33.4 18 26.08 40.3 21

In some embodiments, Form V of Compound 1 is characterized in that ithas two or more peaks in its powder X-ray diffraction pattern selectedfrom those in Table 6. In some embodiments, Form V of Compound 1 ischaracterized in that it has three or more peaks in its powder X-raydiffraction pattern selected from those in Table 6. In some embodiments,Form V of Compound 1 is characterized in that it has four or more peaksin its powder X-ray diffraction pattern selected from those in Table 6.In some embodiments, Form V of Compound 1 is characterized in that ithas five or more peaks in its powder X-ray diffraction pattern selectedfrom those in Table 6. In some embodiments, Form V of Compound 1 ischaracterized in that it has all of the peaks in Table 6 in its X-raydiffraction pattern.

In some embodiments, Form V of Compound 1 is characterized in that ithas one or more peaks in its powder X-ray diffraction pattern selectedfrom those at about 5.85, about 8.23, about 11.02, about 11.15, about12.69, about 13.34, about 16.23, about 16.28, about 17.32, about 18.93,about 23.47, about 24.56, and about 25.40 degrees 2θ. In someembodiments, Form V of Compound 1 is characterized in that it has two ormore peaks in its powder X-ray diffraction pattern selected from thoseat about 5.85, about 8.23, about 11.02, about 11.15, about 12.69, about13.34, about 16.23, about 16.28, about 17.32, about 18.93, about 23.47,about 24.56, and about 25.40 degrees 2θ. In some embodiments, Form V ofCompound 1 is characterized in that it has three or more peaks in itspowder X-ray diffraction pattern selected from those at about 5.85,about 8.23, about 11.02, about 11.15, about 12.69, about 13.34, about16.23, about 16.28, about 17.32, about 18.93, about 23.47, about 24.56,and about 25.40 degrees 2θ. In some embodiments, Form V of Compound 1 ischaracterized in that it has four or more peaks in its powder X-raydiffraction pattern selected from those at about 5.85, about 8.23, about11.02, about 11.15, about 12.69, about 13.34, about 16.23, about 16.28,about 17.32, about 18.93, about 23.47, about 24.56, and about 25.40degrees 2θ. In some embodiments, Form V of Compound 1 is characterizedin that it has five or more peaks in its powder X-ray diffractionpattern selected from those at about 5.85, about 8.23, about 11.02,about 11.15, about 12.69, about 13.34, about 16.23, about 16.28, about17.32, about 18.93, about 23.47, about 24.56, and about 25.40 degrees2θ. In some embodiments, Form V of Compound 1 is characterized in thatit has six or more peaks in its powder X-ray diffraction patternselected from those at about 5.85, about 8.23, about 11.02, about 11.15,about 12.69, about 13.34, about 16.23, about 16.28, about 17.32, about18.93, about 23.47, about 24.56, and about 25.40 degrees 2θ. In someembodiments, Form V of Compound 1 is characterized in that it has sevenor more peaks in its powder X-ray diffraction pattern selected fromthose at about 5.85, about 8.23, about 11.02, about 11.15, about 12.69,about 13.34, about 16.23, about 16.28, about 17.32, about 18.93, about23.47, about 24.56, and about 25.40 degrees 2θ. In some embodiments,Form V of Compound 1 is characterized in that it has eight or more peaksin its powder X-ray diffraction pattern selected from those at about5.85, about 8.23, about 11.02, about 11.15, about 12.69, about 13.34,about 16.23, about 16.28, about 17.32, about 18.93, about 23.47, about24.56, and about 25.40 degrees 2θ. In some embodiments, Form V ofCompound 1 is characterized in that it has nine or more peaks in itspowder X-ray diffraction pattern selected from those at about 5.85,about 8.23, about 11.02, about 11.15, about 12.69, about 13.34, about16.23, about 16.28, about 17.32, about 18.93, about 23.47, about 24.56,and about 25.40 degrees 2θ. In some embodiments, Form V of Compound 1 ischaracterized in that it has ten or more peaks in its powder X-raydiffraction pattern selected from those at about 5.85, about 8.23, about11.02, about 11.15, about 12.69, about 13.34, about 16.23, about 16.28,about 17.32, about 18.93, about 23.47, about 24.56, and about 25.40degrees 2θ. In some embodiments, Form V of Compound 1 is characterizedin that it has eleven or more peaks in its powder X-ray diffractionpattern selected from those at about 5.85, about 8.23, about 11.02,about 11.15, about 12.69, about 13.34, about 16.23, about 16.28, about17.32, about 18.93, about 23.47, about 24.56, and about 25.40 degrees2θ. In some embodiments, Form V of Compound 1 is characterized in thatit has twelve or more peaks in its powder X-ray diffraction patternselected from those at about 5.85, about 8.23, about 11.02, about 11.15,about 12.69, about 13.34, about 16.23, about 16.28, about 17.32, about18.93, about 23.47, about 24.56, and about 25.40 degrees 2θ. In someembodiments, Form V of Compound 1 is characterized in that it has allthirteen peaks in its powder X-ray diffraction pattern selected fromthose at about 5.85, about 8.23, about 11.02, about 11.15, about 12.69,about 13.34, about 16.23, about 16.28, about 17.32, about 18.93, about23.47, about 24.56, and about 25.40 degrees 2θ.

In some embodiments, Form V of Compound 1 is characterized in that ithas one or more peaks in its powder X-ray diffraction pattern selectedfrom those at about 8.0, about 11.0, about 12.7, about 13.3, about 16.3,about 17.9, about 20.3, about 22.6, about 23.5, and about 24.6 degrees2θ.

In some embodiments, the present invention provides a solvatedcrystalline form of Compound 1 referred to as Form VI. In someembodiments, the present invention provides Form VI of Compound 1,having a powder X-ray diffraction pattern substantially similar to thatdepicted in FIG. 11A. In some embodiments, the present inventionprovides Form VI of Compound 1, having a powder X-ray diffractionpattern substantially similar to that depicted in FIG. 11B. In someembodiments, Form VI of Compound 1 is characterized in that it has apeaks in its powder X-ray diffraction pattern selected from those inTable 7 below.

TABLE 7 Compound 1 Form VI XRPD Peaks Relative Position (°2θ) Height(cts) Intensity (%) 10.19 142.1 100

In some embodiments, Form VI of Compound 1 is characterized in that ithas a peak at about 10.19 degrees 2θ in its powder X-ray diffractionpattern.

In some embodiments, Form VI is characterized by an X-ray powderdiffractogram comprising the following peaks: 18.0, 23.4, and25.3°2θ±0.2°2θ, as determined on a diffractometer using Cu—Kα radiationat a wavelength of 1.54 Å. The diffractogram comprises additional peaksat 10.5, 14.2, 15.1, and 18.8°2θ±0.2°2θ. Compound 1 Form VI is alsocharacterized by its X-ray diffraction pattern as substantially shown inFIG. 11A. Compound 1 Form VI is also characterized by its X-raydiffraction pattern as substantially shown in FIG. 11B.

In some embodiments, Form VI of Compound 1 is characterized by adifferential scanning calorimetry (DSC) curve that comprises anendotherms at 131° C., 193° C., and 205° C. Form VI of Compound 1 isalso characterized by its DSC curve as substantially shown in FIG. 12.

In some embodiments, Form VI of Compound 1 is characterized by athermogravimetric analysis (TGA) curve as substantially shown in FIG.13.

In some embodiments, the present invention provides a polymorphic formof Compound 1 referred to as Form VII. In some embodiments, the presentinvention provides Form VII of Compound 1, having a powder X-raydiffraction pattern substantially similar to that depicted in FIG. 14.In some embodiments, Form VII of Compound 1 is characterized in that ithas one or more peaks in its powder X-ray diffraction pattern selectedfrom those in Table 8 below.

TABLE 8 Compound 1 Form VII XRPD Peaks Relative Position (°2θ) Height(cts) Intensity (%) 8.94 175.4 46 9.16 381.3 100 13.73 126.6 33.19 14.7438.9 10.19 17.05 37.7 9.9 17.90 35.0 9.17 18.22 24.2 6.35 18.38 82.521.64 19.47 64.5 16.92 19.51 39.6 10.37 22.37 43.3 11.36 23.85 35.8 9.3923.94 24.2 6.36 25.53 37.8 9.9 25.96 137.4 36.03 27.17 38.5 10.1 27.7638.5 10.1

In some embodiments, Form VII of Compound 1 is characterized in that ithas two or more peaks in its powder X-ray diffraction pattern selectedfrom those in Table 8. In some embodiments, Form VII of Compound 1 ischaracterized in that it has three or more peaks in its powder X-raydiffraction pattern selected from those in Table 8. In some embodiments,Form VII of Compound 1 is characterized in that it has four or morepeaks in its powder X-ray diffraction pattern selected from those inTable 8. In some embodiments, Form VII of Compound 1 is characterized inthat it has five or more peaks in its powder X-ray diffraction patternselected from those in Table 8. In some embodiments, Form VII ofCompound 1 is characterized in that it has all of the peaks in Table 8in its X-ray diffraction pattern.

In some embodiments, Form VII of Compound 1 is characterized in that ithas one or more peaks in its powder X-ray diffraction pattern selectedfrom those at about 8.94, about 17.90, and about 27.76 degrees 2θ; inaddition to having one or more peaks selected from about 9.16, about13.73, about 14.74, about 17.05, about 18.22, about 18.38, about 19.47,about 19.51, about 22.37, about 23.85, about 23.94, about 25.53, about25.96, and about 27.17 degrees 2θ. In some embodiments, Form VII ofCompound 1 is characterized in that it has two or more peaks in itspowder X-ray diffraction pattern selected from those at about 8.94,about 17.90, and about 27.76 degrees 2θ; in addition to having one ormore peaks selected from about 9.16, about 13.73, about 14.74, about17.05, about 18.22, about 18.38, about 19.47, about 19.51, about 22.37,about 23.85, about 23.94, about 25.53, about 25.96, and about 27.17degrees 2θ. In some embodiments, Form VII of Compound 1 is characterizedin that it has one or more peaks in its powder X-ray diffraction patternselected from those at about 8.94, about 17.90, and about 27.76 degrees2θ; in addition to having a peak at about 25.96 degrees 2θ. In someembodiments, Form VII of Compound 1 is characterized in that it has oneor more peaks in its powder X-ray diffraction pattern selected fromthose at about 8.94, and about 27.76 degrees 2θ; in addition to having apeak at about 25.96 degrees 2θ. In some embodiments, Form VII ofCompound 1 is characterized in that it has all three peaks in its powderX-ray diffraction pattern selected from those at about 8.94, about27.76, and about 25.96 degrees 2θ.

In some embodiments, Form VII of Compound 1 is characterized in that ithas one or more peaks in its powder X-ray diffraction pattern selectedfrom those at about 9.2, about 13.7, about 14.7, about 17.1, about 18.4,about 19.5, about 22.4, about 23.9, about 25.5, and about 26.0 degrees2θ.

In some embodiments, the present invention provides a polymorphic formof Compound 1 referred to as Form VIII. In some embodiments, the presentinvention provides Form VIII of Compound 1, having a powder X-raydiffraction pattern substantially similar to that depicted in FIG. 15A.In some embodiments, the present invention provides Form VIII ofCompound 1, having a powder X-ray diffraction pattern substantiallysimilar to that depicted in FIG. 15B. In some embodiments, Form VIII ofCompound 1 is characterized in that it has one or more peaks in itspowder X-ray diffraction pattern selected from those in Table 9 below.

TABLE 9 Compound 1 Form VIII XRPD Peaks Relative Position (°2θ) Height(cts) Intensity (%) 5.50 18.8 24.4 8.95 28.2 36.6 10.31 42.4 54.9 12.9016.6 21.5 15.82 77.2 100.0 17.84 27.3 35.4 18.77 36.3 47.0 20.40 54.070.0 22.23 25.3 32.8 22.71 43.4 56.2 25.83 32.6 42.2 27.73 22.5 29.2

In some embodiments, Form VIII of Compound 1 is characterized in that ithas two or more peaks in its powder X-ray diffraction pattern selectedfrom those in Table 9. In some embodiments, Form VIII of Compound 1 ischaracterized in that it has three or more peaks in its powder X-raydiffraction pattern selected from those in Table 9. In some embodiments,Form VIII of Compound 1 is characterized in that it has four or morepeaks in its powder X-ray diffraction pattern selected from those inTable 9. In some embodiments, Form VIII of Compound 1 is characterizedin that it has five or more peaks in its powder X-ray diffractionpattern selected from those in Table 9. In some embodiments, Form VIIIof Compound 1 is characterized in that it has all of the peaks in Table9 in its X-ray diffraction pattern.

In some embodiments, Form VIII of Compound 1 is characterized in that ithas one or more peaks in its powder X-ray diffraction pattern selectedfrom those at about 5.50, about 10.31, about 18.77, about 22.23, andabout 25.83 degrees 2θ. In some embodiments, Form VIII of Compound 1 ischaracterized in that it has two or more peaks in its powder X-raydiffraction pattern selected from those at about 5.50, about 10.31,about 18.77, about 22.23, and about 25.83 degrees 2θ. In someembodiments, Form VIII of Compound 1 is characterized in that it hasthree or more peaks in its powder X-ray diffraction pattern selectedfrom those at about 5.50, about 10.31, about 18.77, about 22.23, andabout 25.83 degrees 2θ. In some embodiments, Form VIII of Compound 1 ischaracterized in that it has four or more peaks in its powder X-raydiffraction pattern selected from those at about 5.50, about 10.31,about 18.77, about 22.23, and about 25.83 degrees 2θ. In someembodiments, Form VIII of Compound 1 is characterized in that it has allfive peaks in its powder X-ray diffraction pattern selected from thoseat about 5.50, about 10.31, about 18.77, about 22.23, and about 25.83degrees 2θ.

In some embodiments, Form VIII of Compound 1 is characterized in that ithas one or more peaks in its powder X-ray diffraction pattern selectedfrom those at about 5.5, about 10.3, about 15.8, about 18.8, about 20.4,about 22.7, and about 25.8 degrees 2θ.

In some embodiments, Form VIII is characterized by an X-ray powderdiffractogram comprising the following peaks: 16.0, 20.5, and22.8°2θ±0.2°2θ, as determined on a diffractometer using Cu—Kα radiationat a wavelength of 1.54 Å. The diffractogram comprises additional peaksat 9.1, 10.5, 18.8, and 25.8°2θ±0.2°2θ. Compound 1 Form VIII is alsocharacterized by its X-ray diffraction pattern as substantially shown inFIG. 15A. Compound 1 Form VIII is also characterized by its X-raydiffraction pattern as substantially shown in FIG. 15B.

In some embodiments, Form VIII of Compound 1 is characterized by adifferential scanning calorimetry (DSC) curve that comprises anendotherm at 205° C. Form VIII of Compound 1 is also characterized byits DSC curve as substantially shown in FIG. 16.

In some embodiments, Form VIII of Compound 1 is characterized by athermogravimetric analysis (TGA) curve as substantially shown in FIG.17.

Some embodiments herein provide for a crystalline form of a sodium saltor co-crystal of Compound 1, which is referred to as Compound 1 SodiumForm I. In some embodiments, Compound 1 Sodium Form I is characterizedby an X-ray powder diffractogram comprising the following peaks: 7.5,8.2, 20.4, and 20.9°2θ±0.2°2θ, as determined on a diffractometer usingCu—Kα radiation at a wavelength of 1.54 Å. The diffractogram comprisesadditional peaks at 14.8, 17.5, 24.0, and 27.7°2θ±0.2°2θ. Compound 1Sodium Form I is also characterized by its full X-ray diffractionpattern as substantially shown in FIG. 19.

In some embodiments, Compound 1 Sodium Form I is characterized by adifferential scanning calorimetry (DSC) curve that comprises anendotherm at about 37° C. and an endotherm at about 283° C. Compound 1Sodium Form I also is characterized by its DSC curve as substantiallyshown in FIG. 20.

In some embodiments, Compound 1 Sodium Form I is characterized by athermogravimetric analysis (TGA) curve as substantially shown in FIG.21.

Some embodiments herein provide for a crystalline form of a sodium saltor co-crystal of Compound 1, which is referred to as Compound 1 SodiumForm II. In some embodiments, Compound 1 Sodium Form II is characterizedby an X-ray powder diffractogram comprising the following peaks: 4.8,6.7, 15.6, and 24.2°2θ±0.2°2θ, as determined on a diffractometer usingCu—Kα radiation at a wavelength of 1.54 Å. The diffractogram comprisesadditional peaks at 17.9, 29.2, 32.5, and 38.0°2θ±0.2°2θ. Compound 1Sodium Form II is also characterized by its full X-ray diffractionpattern as substantially shown in FIG. 22.

In some embodiments, Compound 1 Sodium Form II is characterized by adifferential scanning calorimetry (DSC) curve that comprises anendotherm at about 19° C., an endotherm at about 78° C., and anendotherm at about 136° C. Compound 1 Sodium Form II also ischaracterized by its DSC curve as substantially shown in FIG. 23.

In some embodiments, Compound 1 Sodium Form II is characterized by athermogravimetric analysis (TGA) curve as substantially shown in FIG.24.

Some embodiments herein provide for a crystalline form of a calcium saltor co-crystal of Compound 1, which is referred to as Compound 1 CalciumForm I. In some embodiments, Compound 1 Calcium Form I is characterizedby an X-ray powder diffractogram comprising the following peaks: 10.1,14.3, and 20.4°2θ±0.2°2θ, as determined on a diffractometer using Cu—Kαradiation at a wavelength of 1.54 Å. The diffractogram comprisesadditional peaks at 3.6, 7.8, 21.6, 27.3, 28.9°2θ±0.2°2θ. Compound 1Calcium Form I is also characterized by its full X-ray diffractionpattern as substantially shown in FIG. 25.

In some embodiments, Compound 1 Calcium Form I is characterized by adifferential scanning calorimetry (DSC) curve that comprises anendotherm at about 17° C., an endotherm at about 72° C., an endotherm atabout 180° C., and an endotherm at about 202° C. Compound 1 Calcium FormI also is characterized by its DSC curve as substantially shown in FIG.26.

In some embodiments, Compound 1 Calcium Form I is characterized by athermogravimetric analysis (TGA) curve as substantially shown in FIG.27.

Some embodiments herein provide for a crystalline form of a magnesiumsalt or co-crystal of Compound 1, which is referred to as Compound 1Magnesium Form I. In some embodiments, Compound 1 Magnesium Form I ischaracterized by an X-ray powder diffractogram comprising the followingpeaks: 8.2, 16.9, 19.1, and 21.2°2θ±0.2°2θ, as determined on adiffractometer using Cu—Kα radiation at a wavelength of 1.54 Å. Thediffractogram comprises additional peaks at 15.8, 24.1, 26.1, and27.1°2θ±0.2°02. Compound 1 Magnesium Form I is also characterized by itsfull X-ray diffraction pattern as substantially shown in FIG. 28.

In some embodiments, Compound 1 Magnesium Form I is characterized by adifferential scanning calorimetry (DSC) curve that comprises anendotherm at about 53° C. Compound 1 Magnesium Form I also ischaracterized by its DSC curve as substantially shown in FIG. 29.

In some embodiments, Compound 1 Magnesium Form I is characterized by athermogravimetric analysis (TGA) curve as substantially shown in FIG.30.

Some embodiments herein provide for a crystalline form of adiethanolamine salt or co-crystal of Compound 1, which is referred to asCompound 1 Diethanolamine Form I. In some embodiments, Compound 1Diethanolamine Form I is characterized by an X-ray powder diffractogramcomprising the following peaks: 5.1, 8.0, 17.0, 25.1°2θ±0.2°2θ, asdetermined on a diffractometer using Cu—Kα radiation at a wavelength of1.54 Å. The diffractogram comprises additional peaks at 13.4, 16.4,20.4, and 22.6°2θ±0.2°2θ. Compound 1 Diethanolamine Form I is alsocharacterized by its full X-ray diffraction pattern as substantiallyshown in FIG. 31.

In some embodiments, Compound 1 Diethanolamine Form I is characterizedby a differential scanning calorimetry (DSC) curve that comprises anendotherm at about 118° C. Compound 1 Diethanolamine Form I also ischaracterized by its DSC curve as substantially shown in FIG. 32.

In some embodiments, Compound 1 Diethanolamine Form I is characterizedby a thermogravimetric analysis (TGA) curve as substantially shown inFIG. 33.

Some embodiments herein provide for a crystalline form of a piperazinesalt or co-crystal of Compound 1, which is referred to as Compound 1Piperazine Form I. In some embodiments, Compound 1 Piperazine Form I ischaracterized by an X-ray powder diffractogram comprising the followingpeaks: 5.6, 8.0, 10.5, and 15.9°2θ±0.2°2θ, as determined on adiffractometer using Cu—Kα radiation at a wavelength of 1.54 Å. Thediffractogram comprises additional peaks at 13.3, 17.9, 22.1, and24.3°2θ±0.2°2θ. Compound 1 Piperazine Form I is also characterized byits full X-ray diffraction pattern as substantially shown in FIG. 34.

In some embodiments, Compound 1 Piperazine Form I is characterized by adifferential scanning calorimetry (DSC) curve that comprises anendotherm at about 27° C. and an endotherm at about 139° C. Compound 1Piperazine Form I also is characterized by its DSC curve assubstantially shown in FIG. 35.

In some embodiments, Compound 1 Piperazine Form I is characterized by athermogravimetric analysis (TGA) curve as substantially shown in FIG.36.

3. Compounds and Definitions

Compounds of this invention include those described generally above, andare further illustrated by the classes, subclasses, and speciesdisclosed herein. As used herein, the following definitions shall applyunless otherwise indicated. For purposes of this invention, the chemicalelements are identified in accordance with the Periodic Table of theElements, CAS version, Handbook of Chemistry and Physics, 75^(th) Ed.Additionally, general principles of organic chemistry are described in“Organic Chemistry” Thomas Sorrell, University Science Books, Sausalito:1999, and “March's Advanced Organic Chemistry”, 5^(th) Ed., Ed.: Smith,M. B. and March, J., John Wiley & Sons, New York: 2001, the entirecontents of which are hereby incorporated by reference.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation, or a monocyclic hydrocarbonor bicyclic hydrocarbon that is completely saturated or that containsone or more units of unsaturation, but which is not aromatic (alsoreferred to herein as “carbocycle,” “cycloaliphatic” or “cycloalkyl”),that has a single point of attachment to the rest of the molecule.Unless otherwise specified, aliphatic groups contain 1-6 aliphaticcarbon atoms. In some embodiments, aliphatic groups contain 1-5aliphatic carbon atoms. In other embodiments, aliphatic groups contain1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groupscontain 1-3 aliphatic carbon atoms, and in yet other embodiments,aliphatic groups contain 1-2 aliphatic carbon atoms. In someembodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refersto a monocyclic C₃-C₆ hydrocarbon that is completely saturated or thatcontains one or more units of unsaturation, but which is not aromatic,that has a single point of attachment to the rest of the molecule.Suitable aliphatic groups include, but are not limited to, linear orbranched, substituted or unsubstituted alkyl, alkenyl, alkynyl groupsand hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or(cycloalkyl)alkenyl.

The term “lower alkyl” refers to a C₁₋₄ straight or branched alkylgroup. Exemplary lower alkyl groups are methyl, ethyl, propyl,isopropyl, butyl, isobutyl, and tert-butyl.

The term “lower haloalkyl” refers to a C₁₋₄ straight or branched alkylgroup that is substituted with one or more halogen atoms.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon (including, any oxidized form of nitrogen,sulfur, phosphorus, or silicon; the quaternized form of any basicnitrogen or; a substitutable nitrogen of a heterocyclic ring, forexample N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) orNR⁺ (as in N-substituted pyrrolidinyl)).

The term “unsaturated,” as used herein, means that a moiety has one ormore units of unsaturation.

As used herein, the term “bivalent C₁₋₈ (or C₁₋₆) saturated orunsaturated, straight or branched, hydrocarbon chain”, refers tobivalent alkylene, alkenylene, and alkynylene chains that are straightor branched as defined herein.

The term “alkylene” refers to a bivalent alkyl group. An “alkylenechain” is a polymethylene group, i.e., —(CH₂)_(n)—, wherein n is apositive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylenegroup in which one or more methylene hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

The term “alkenylene” refers to a bivalent alkenyl group. A substitutedalkenylene chain is a polymethylene group containing at least one doublebond in which one or more hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

“Alkoxy” refers to the group “alkyl-O—”. Examples of alkoxy groupsinclude methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy,sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

The term “halogen” means F, Cl, Br, or I.

The term “ring” means a cycloalkyl group or heterocyclic ring as definedherein.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic orbicyclic ring systems having a total of five to fourteen ring members,wherein at least one ring in the system is aromatic and wherein eachring in the system contains 3 to 7 ring members. The term “aryl” may beused interchangeably with the term “aryl ring.”

The term “aryl” used alone or as part of a larger moiety as in“aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic andbicyclic ring systems having a total of five to 10 ring members, whereinat least one ring in the system is aromatic and wherein each ring in thesystem contains three to seven ring members. The term “aryl” may be usedinterchangeably with the term “aryl ring”. In certain embodiments of thepresent invention, “aryl” refers to an aromatic ring system whichincludes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl andthe like, which may bear one or more substituents. Also included withinthe scope of the term “aryl,” as it is used herein, is a group in whichan aromatic ring is fused to one or more non-aromatic rings, such asindanyl, phthalimidyl, naphthimidyl, phenanthridinyl, ortetrahydronaphthyl, and the like.

The term “aralkyl” refers to aryl-alkylene, wherein aryl and alkyleneare as defined herein.

The term “aralkoxy” refers to aryl-alkoxy, wherein aryl and alkoxy areas defined herein.

The term “aryloxyalkyl” refers to aryl-O-alkylene, wherein aryl andalkylene are as defined herein.

The terms “heteroaryl” and “heteroar-,” used alone or as part of alarger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer togroups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms;having 6, 10, or 14 π electrons shared in a cyclic array; and having, inaddition to carbon atoms, from one to five heteroatoms. Heteroarylgroups include, without limitation, thienyl, furanyl, pyrrolyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl,oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl,naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar-”,as used herein, also include groups in which a heteroaromatic ring isfused to one or more aryl, cycloaliphatic, or heterocyclyl rings, wherethe radical or point of attachment is on the heteroaromatic ring.Nonlimiting examples include indolyl, isoindolyl, benzothienyl,benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl,quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl,quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl,phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Aheteroaryl group may be mono- or bicyclic. The term “heteroaryl” may beused interchangeably with the terms “heteroaryl ring,” “heteroarylgroup,” or “heteroaromatic,” any of which terms include rings that areoptionally substituted. The term “heteroaralkyl” refers to an alkylgroup substituted by a heteroaryl, wherein the alkyl and heteroarylportions independently are optionally substituted.

As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclicradical,” and “heterocyclic ring” are used interchangeably and refer toa stable 5- to 7-membered monocyclic or 7 to 10-membered bicyclicheterocyclic moiety that is either saturated or partially unsaturated,and having, in addition to carbon atoms, one or more, preferably one tofour, heteroatoms, as defined above. When used in reference to a ringatom of a heterocycle, the term “nitrogen” includes a substitutednitrogen. As an example, in a saturated or partially unsaturated ringhaving 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, thenitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as inpyrrolidinyl), or +NR (as in N-substituted pyrrolidinyl).

A heterocyclic ring can be attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure and any ofthe ring atoms can be optionally substituted. Examples of such saturatedor partially unsaturated heterocyclic radicals include, withoutlimitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl,piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. Theterms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclicgroup,” “heterocyclic moiety,” and “heterocyclic radical,” are usedinterchangeably herein, and also include groups in which a heterocyclylring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings,such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, ortetrahydroquinolinyl, where the radical or point of attachment is on theheterocyclyl ring. A heterocyclyl group may be mono- or bicyclic. Theterm “heterocyclylalkyl” refers to an alkyl group substituted by aheterocyclyl, wherein the alkyl and heterocyclyl portions independentlyare optionally substituted.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond. The term “partiallyunsaturated” is intended to encompass rings having multiple sites ofunsaturation, but is not intended to include aryl or heteroarylmoieties, as herein defined.

As described herein, compounds of the invention may contain “optionallysubstituted” moieties. In general, the term “substituted,” whetherpreceded by the term “optionally” or not, means that one or morehydrogens of the designated moiety are replaced with a suitablesubstituent. Unless otherwise indicated, an “optionally substituted”group may have a suitable substituent at each substitutable position ofthe group, and when more than one position in any given structure may besubstituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds. The term “stable,” as used herein, refers tocompounds that are not substantially altered when subjected toconditions to allow for their production, detection, and, in certainembodiments, their recovery, purification, and use for one or more ofthe purposes disclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group are independently halogen;—(CH₂)₀₋₄R^(∘); —(CH₂)₀₋₄OR^(∘); —O(CH₂)₀₋₄R^(∘), —O—(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄CH(OR^(∘))₂; —(CH₂)₀₋₄SR^(∘); —(CH₂)₀₋₄Ph, which may besubstituted with R^(∘); —(CH₂)₀₋₄O(CH₂)₀₋₁Ph which may be substitutedwith R^(∘); —CH═CHPh, which may be substituted with R^(∘);—(CH₂)₀₋₄O(CH₂)₀₋₁-pyridyl which may be substituted with R^(∘); —NO₂;—CN; —N₃; —(CH₂)₀₋₄N(R^(∘))₂; —(CH₂)₀₋₄N(R^(∘))C(O)R^(∘);—N(R^(∘))C(S)R^(∘); —(CH₂)₀₋₄N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))C(S)NR^(∘)₂; —(CH₂)₀₋₄N(R^(∘))C(O)OR^(∘); —N(R^(∘))N(R^(∘))C(O)R^(∘);—N(R^(∘))N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))N(R^(∘))C(O)OR^(∘);—(CH₂)₀₋₄C(O)R^(∘); —C(S)R^(∘); —(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄C(O)SR^(∘); —(CH₂)₀₋₄C(O)OSiR^(∘) ₃; —(CH₂)₀₋₄OC(O)R^(∘);—OC(O)(CH₂)₀₋₄SR^(∘)—; —(CH₂)₀₋₄SC(O)R^(∘); —(CH₂)₀₋₄C(O)NR^(∘) ₂;—C(S)NR^(∘) ₂; —C(S)SR^(∘); —SC(S)SR^(∘), —(CH₂)₀₋₄OC(O)NR^(∘) ₂;—C(O)N(OR^(∘))R^(∘); —C(O)C(O)R^(∘); —C(O)CH₂C(O)R^(∘);—C(NOR^(∘))R^(∘); —(CH₂)₀₋₄SSR^(∘); —(CH₂)₀₋₄S(O)₂R^(∘);—(CH₂)₀₋₄S(O)₂OR^(∘); —(CH₂)₀₋₄OS(O)₂R^(∘); —S(O)₂NR^(∘) ₂;—(CH₂)₀₋₄S(O)R^(∘); —N(R^(∘))S(O)₂NR^(∘) ₂; —N(R^(∘))S(O)₂R^(∘);—N(OR^(∘))R^(∘); —C(NH)NR^(∘) ₂; —P(O)₂R^(∘); —P(O)R^(∘) ₂; —OP(O)R^(∘)₂; —OP(O)(OR^(∘))₂; SiR^(∘) ₃; —(C₁₋₄ straight or branchedalkylene)O—N(R^(∘))₂; or —(C₁₋₄ straight or branchedalkylene)C(O)O—N(R^(∘))₂, wherein each R^(∘) may be substituted asdefined below and is independently hydrogen, C₁₋₆ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, —CH₂-(5-6 membered heteroaryl ring), or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(∘), taken together with their intervening atom(s), form a3-12-membered saturated, partially unsaturated, or aryl mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, which may be substituted as defined below.

Suitable monovalent substituents on R^(∘) (or the ring formed by takingtwo independent occurrences of R^(∘) together with their interveningatoms), are independently halogen, —(CH₂)₀₋₂R^(●), -(haloR^(●)),—(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(●), —(CH₂)₀₋₂CH(OR^(●))₂, —O(haloR^(●)), —CN,—N₃, —(CH₂)₀₋₂C(O)R^(●), —(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(●),—(CH₂)₀₋₂SR^(●), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(●),—(CH₂)₀₋₂NR^(●) ₂, —NO₂, —SiR^(●) ₃, —OSiR^(●) ₃, —C(O)SR^(●), —(C₁₋₄straight or branched alkylene)C(O)OR^(●), or —SSR^(●); wherein eachR^(●) is unsubstituted or where preceded by “halo” is substituted onlywith one or more halogens, and is independently selected from C₁₋₄aliphatic, —CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. Suitable divalent substituents on asaturated carbon atom of R^(∘) include ═O and ═S.

Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: ═O, ═S, ═NNR*₂,═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*, —O(C(R*2))₂₋₃O—, or—S(C(R*₂))₂₋₃S—, wherein each independent occurrence of R* is selectedfrom hydrogen, C₁₋₆ aliphatic which may be substituted as defined below,or an unsubstituted 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Suitable divalent substituents that are bound tovicinal substitutable carbons of an “optionally substituted” groupinclude: —O(CR*₂)₂₋₃O—, wherein each independent occurrence of R* isselected from hydrogen, C₁₋₆ aliphatic which may be substituted asdefined below, or an unsubstituted 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R* include halogen,—R^(●), -(haloR^(●)), —OH, —OR^(●), —O(haloR^(●)), —CN, —C(O)OH,—C(O)OR^(●), —NH₂, —NHR^(●), —NR^(●) ₂, or —NO₂, wherein each R^(●) isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted” group include —R^(†), —NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†),—C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†), —S(O)₂R^(†), —S(O)₂NR^(†) ₂,—C(S)NR^(†) ₂, —C(NH)NR^(†) ₂, or —N(R^(†))S(O)₂R^(†); wherein eachR^(†) is independently hydrogen, C₁₋₆ aliphatic which may be substitutedas defined below, unsubstituted —OPh, or an unsubstituted 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(†), taken together with their intervening atom(s) form anunsubstituted 3-12-membered saturated, partially unsaturated, or arylmono- or bicyclic ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R^(†) are independentlyhalogen, —R^(●), -(haloR^(●)), —OH, —OR^(●), —O(haloR^(●)), —CN,—C(O)OH, —C(O)OR^(●), —NH₂, —NHR^(●), —NR^(●) ₂, or —NO₂, wherein eachR^(●) is unsubstituted or where preceded by “halo” is substituted onlywith one or more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

The term “co-crystal” refers to a molecular complex of an ionized ornon-ionized Compound 1 (or any other compound disclosed herein) and oneor more non-ionized co-crystal formers (such as a pharmaceuticallyacceptable salt) connected through non-covalent interactions.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge etal., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19, as does the Handbook ofPharmaceutical Salts: Properties, Selection, and Use, 2^(nd) RevisedEdition, P. Heinrich Stahl and Camille G. Wermuth, Eds. Wiley, April,2011, each of which is incorporated herein by reference.Pharmaceutically acceptable salts of the compounds of this inventioninclude those derived from suitable inorganic and organic acids andbases. Examples of pharmaceutically acceptable, nontoxic acid additionsalts are salts of an amino group formed with inorganic acids such ashydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid andperchloric acid or with organic acids such as acetic acid, oxalic acid,maleic acid, tartaric acid, citric acid, succinic acid or malonic acidor by using other methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike.

Salts derived from appropriate bases include metal ions (includingaluminum, zinc, alkali metals, alkaline earth metals), ammonium andN⁺(C₁₋₄alkyl)₄ salts. Representative alkali or alkaline earth metalsalts include sodium, lithium, potassium, calcium, magnesium, and thelike. Further pharmaceutically acceptable salts include, whenappropriate, those derived from nontoxic ammonium, quaternary ammonium,and primary, secondary or tertiary amine cations, including but notlimited to those derived from natural or non-naturally-occurring aminoacids. Representative amine or ammonium-based salts include but are notlimited to those derived from arginine, betaine, hydrabamine, choline,diethylamine, lysine, benzathine, 2-(diethylamino)-ethanol,ethanolamine, 1-(2-hydroxyethyl)-pyrrolidine, diethanolamine, ammonia,deanol, N-methyl-glucamine, tromethamine, triethanolamine,4-(2-hydroxyethyl)-morpholine, 1H-imidazole, ethylenediamine,piperazine, procaine, and benethamine.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, Z and E double bond isomers,and Z and E conformational isomers. Therefore, single stereochemicalisomers as well as enantiomeric, diastereomeric, and geometric (orconformational) mixtures of the present compounds are within the scopeof the invention. Unless otherwise stated, all tautomeric forms of thecompounds of the invention are within the scope of the invention.Additionally, unless otherwise stated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds having thepresent structures including the replacement of hydrogen by deuterium ortritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention. Such compounds are useful, forexample, as analytical tools, as probes in biological assays, or astherapeutic agents in accordance with the present invention.

The term “reaction conditions” is intended to refer to the physicaland/or environmental conditions under which a chemical reactionproceeds. The term “under conditions sufficient to” or “under reactionconditions sufficient to” is intended to refer to the reactionconditions under which the desired chemical reaction can proceed.Examples of reaction conditions include, but are not limited to, one ormore of following: reaction temperature, solvent, pH, pressure, reactiontime, mole ratio of reactants, the presence of a base or acid, orcatalyst, radiation, concentration, etc. Reaction conditions may benamed after the particular chemical reaction in which the conditions areemployed, such as, coupling conditions, hydrogenation conditions,acylation conditions, reduction conditions, etc. Reaction conditions formost reactions are generally known to those skilled in the art or can bereadily obtained from the literature. Exemplary reaction conditionssufficient for performing the chemical transformations provided hereincan be found throughout, and in particular, the examples below. It isalso contemplated that the reaction conditions can include reagents inaddition to those listed in the specific reaction.

4. General Methods for Providing the Present Compounds

The present processes may be performed using methods disclosed hereinand routine modifications thereof which will be apparent given thedisclosure herein and methods well known in the art. Conventional andwell-known synthetic methods may be used in addition to the teachingsherein. The synthesis of typical compounds described herein, e.g.compounds having structures described by Compound 1, or other formulasor compounds disclosed herein (i.e. I, G-1, G-1-a, G-2, G-2-a, G-2-b,G-3, G-3-b, G-4, G-4-a, G-4-b, G-5, G-5-a, G-6, G-6-a, G-7, G-7-a, G-8,G-8-a, G-8-b, G-9, G-9-a, G-10, G-11, G-12, G-13, G-13-a, etc.) may beaccomplished as described in the following examples. If available,reagents may be purchased commercially, e.g. from Sigma Aldrich or otherchemical suppliers.

Typical embodiments of compounds in accordance with the presentdisclosure may be synthesized using the general reaction schemesdescribed below. It will be apparent given the description herein thatthe general schemes may be altered by substitution of the startingmaterials with other materials having similar structures to result inproducts that are correspondingly different. Descriptions of synthesesfollow to provide numerous examples of how the starting materials mayvary to provide corresponding products. Given a desired product forwhich the substituent groups are defined, the necessary startingmaterials generally may be determined by inspection. Starting materialsare typically obtained from commercial sources or synthesized usingpublished methods. For synthesizing compounds which are embodiments ofthe present disclosure, inspection of the structure of the compound tobe synthesized will provide the identity of each substituent group. Theidentity of the final product will generally render apparent theidentity of the necessary starting materials by a simple process ofinspection, given the examples herein.

The compounds of this disclosure can be prepared from readily availablestarting materials using, for example, the following general methods andprocedures. It will be appreciated that where typical or preferredprocess conditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given, other process andpurification conditions can also be used unless otherwise stated.Optimum reaction conditions may vary with the particular reactants orsolvent used, but such conditions can be determined by one skilled inthe art by routine optimization procedures.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. Suitableprotecting groups for various functional groups as well as suitableconditions for protecting and deprotecting particular functional groupsare well known in the art. For example, numerous protecting groups aredescribed in T. W. Greene and G. M. Wuts (1999) Protecting Groups inOrganic Synthesis, 3rd Edition, Wiley, New York, and references citedtherein.

Furthermore, the compounds of this disclosure may contain one or morechiral centers. Accordingly, if desired, such compounds can be preparedor isolated as pure stereoisomers, i.e., as individual enantiomers ordiastereomers or as stereoisomer-enriched mixtures. All suchstereoisomers (and enriched mixtures) are included within the scope ofthis disclosure, unless otherwise indicated. Pure stereoisomers (orenriched mixtures) may be prepared using, for example, optically activestarting materials or stereoselective reagents well-known in the art.Alternatively, racemic mixtures of such compounds can be separatedusing, for example, chiral column chromatography, chiral resolvingagents, and the like.

The starting materials for the following reactions are generally knowncompounds or can be prepared by known procedures or obviousmodifications thereof. For example, many of the starting materials areavailable from commercial suppliers such as Aldrich Chemical Co.(Milwaukee, Wis., USA), Bachem (Torrance, Calif., USA), Emka-Chemce orSigma (St. Louis, Mo., USA). Others may be prepared by procedures orobvious modifications thereof, described in standard reference textssuch as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15(John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds,Volumes 1-5, and Supplementals (Elsevier Science Publishers, 1989)organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March'sAdvanced Organic Chemistry, (John Wiley, and Sons, 5^(th) Edition,2001), and Larock's Comprehensive Organic Transformations (VCHPublishers Inc., 1989).

The terms “solvent,” “inert organic solvent” or “inert solvent” refer toa solvent inert under the conditions of the reaction being described inconjunction therewith (including, for example, benzene, toluene,acetonitrile, tetrahydrofuran (“THF”), 2-methyltetrahydrofuran(“MeTHF”), dimethylformamide (“DMF”), chloroform, methylene chloride (ordichloromethane), diethyl ether, methanol, 2-propanol, pyridine and thelike). Unless specified to the contrary, the solvents used in thereactions of the present disclosure are inert organic solvents, and thereactions are carried out under an inert gas, preferably nitrogen.

In each of the exemplary schemes it may be advantageous to separatereaction products from one another and/or from starting materials. Thedesired products of each step or series of steps is separated and/orpurified (hereinafter separated) to the desired degree of homogeneity bythe techniques common in the art. Typically such separations involvemultiphase extraction, crystallization from a solvent or solventmixture, distillation, sublimation, or chromatography. Chromatographycan involve any number of methods including, for example: reverse-phaseand normal phase; size exclusion; ion exchange; high, medium, and lowpressure liquid chromatography methods and apparatus; small scaleanalytical; simulated moving bed (SMB) and preparative thin or thicklayer chromatography, as well as techniques of small scale thin layerand flash chromatography.

Another class of separation methods involves treatment of a mixture witha reagent selected to bind to or render otherwise separable a desiredproduct, unreacted starting material, reaction by product, or the like.Such reagents include adsorbents or absorbents such as activated carbon,molecular sieves, ion exchange media, or the like. Alternatively, thereagents can be acids in the case of a basic material, bases in the caseof an acidic material, binding reagents such as antibodies, bindingproteins, selective chelators such as crown ethers, liquid/liquid ionextraction reagents (LIX), or the like.

Selection of appropriate methods of separation depends on the nature ofthe materials involved. For example, boiling point, and molecular weightin distillation and sublimation, presence or absence of polar functionalgroups in chromatography, stability of materials in acidic and basicmedia in multiphase extraction, and the like. One skilled in the artwill apply techniques most likely to achieve the desired separation.

A single stereoisomer, e.g., an enantiomer, substantially free of itsstereoisomer may be obtained by resolution of the racemic mixture usinga method such as formation of diastereomers using optically activeresolving agents (Stereochemistry of Carbon Compounds, (1962) by E. L.Eliel, McGraw Hill; Lochmuller, C. H., (1975) J. Chromatogr., 113, 3)283-302). Racemic mixtures of chiral compounds of the disclosure can beseparated and isolated by any suitable method, including: (1) formationof ionic, diastereomeric salts with chiral compounds and separation byfractional crystallization or other methods, (2) formation ofdiastereomeric compounds with chiral derivatizing reagents, separationof the diastereomers, and conversion to the pure stereoisomers, and (3)separation of the substantially pure or enriched stereoisomers directlyunder chiral conditions.

Under method (1), diastereomeric salts can be formed by reaction ofenantiomerically pure chiral bases such as brucine, quinine, ephedrine,strychnine, α-methyl-β-phenylethylamine (amphetamine), and the like withasymmetric compounds bearing acidic functionality, such as carboxylicacid and sulfonic acid. The diastereomeric salts may be induced toseparate by fractional crystallization or ionic chromatography. Forseparation of the optical isomers of amino compounds, addition of chiralcarboxylic or sulfonic acids, such as camphorsulfonic acid, tartaricacid, mandelic acid, or lactic acid can result in formation of thediastereomeric salts.

Alternatively, by method (2), the substrate to be resolved is reactedwith one enantiomer of a chiral compound to form a diastereomeric pair(Eliel, E. and Wilen, S. (1994) Stereochemistry of Organic Compounds,John Wiley & Sons, Inc., p. 322). Diastereomeric compounds can be formedby reacting asymmetric compounds with enantiomerically pure chiralderivatizing reagents, such as menthyl derivatives, followed byseparation of the diastereomers and hydrolysis to yield the free,enantiomerically enriched substrate. A method of determining opticalpurity involves making chiral esters, such as a menthyl ester, e.g., (−)menthyl chloroformate in the presence of base, or Mosher ester,α-methoxy-α-(trifluoromethyl)phenyl acetate (Jacob III. (1982) J. Org.Chem. 47:4165), of the racemic mixture, and analyzing the NMR spectrumfor the presence of the two atropisomeric diastereomers. Stablediastereomers of atropisomeric compounds can be separated and isolatedby normal- and reverse-phase chromatography following methods forseparation of atropisomeric naphthyl-isoquinolines (Hoye, T., WO96/15111). By method (3), a racemic mixture of two enantiomers can beseparated by chromatography using a chiral stationary phase (ChiralLiquid Chromatography (1989) W. J. Lough, Ed. Chapman and Hall, NewYork; Okamoto, (1990) J. of Chromatogr. 513:375-378). Enriched orpurified enantiomers can be distinguished by methods used to distinguishother chiral molecules with asymmetric carbon atoms, such as opticalrotation and circular dichroism.

In some embodiments, compounds of the present invention of formula I(including, but not limited to Compound 1) can be generally preparedaccording to the method described in 2013/0123231 A1, the entirety ofwhich is incorporated herein by reference.

In some embodiments, the present invention provides synthetic methodsand synthetic intermediates for the production of compounds of formulaI:

or a pharmaceutically acceptable salt or agriculturally acceptable saltthereof, wherein:

-   R^(a) is an optionally substituted group selected from a 3-7    membered ring having 0-2 heteroatoms selected from nitrogen, oxygen,    and sulfur, and a C₁₋₆ aliphatic;-   R² is hydrogen, or optionally substituted C₁₋₆ aliphatic; and-   R⁵ is hydrogen or halogen.

As defined generally above, R^(a) is an optionally substituted groupselected from 3-7 membered ring and a C₁₋₆ aliphatic. In someembodiments, R^(a) is an optionally substituted 3-7 membered ring. Insome embodiments, R^(a) is an optionally substituted 6-memberedmonocyclic ring. In some embodiments, R^(a) is an optionally substituted6-membered monocyclic heterocyclic ring. In some embodiments, R^(a) istetrahydropyranyl. In some embodiments, R^(a) is tetrahydropyran-4-yl.In some embodiments, R^(a) is an optionally substituted C₁₋₆ aliphaticgroup. In some embodiments, R^(a) is an optionally substituted C₁₋₆alkyl group.

As defined generally above, R² is hydrogen, or optionally substitutedC₁₋₆ aliphatic. In some embodiments, R² is hydrogen. In someembodiments, R² is optionally substituted C₁₋₆ aliphatic. In someembodiments, R² is optionally substituted C₁₋₆ alkyl. In someembodiments, R² is C₁₋₆ alkyl. In some embodiments, R² is methyl.

As defined generally above R⁵ is hydrogen or halogen. In someembodiments, R⁵ is hydrogen. In some embodiments, R⁵ is halogen. In someembodiments fluoro.

In some embodiments, compounds of formula I are prepared according themethod depicted in Scheme 1, wherein each of R^(a), R^(e), R², R⁵ are asdefined in classes and subclasses herein, both singly and incombination.

As used herein, R^(H) is a leaving group. In some embodiments, R^(H) isa halogen or sulfonate. In some embodiments, R^(H) is a halogen. In someembodiments, R^(H) is chloro. In some embodiments, R^(H) is bromo. Insome embodiments, R^(H) is iodo. In some embodiments, R^(H) is asulfonate. In some embodiments, R^(H) is a mesylate, a triflate, abenzenesulfonate, a tosylate, a brosylate, or a nosylate.

As used herein, R^(e) is a carboxyl protecting group. In someembodiments, R^(e) is —Si(R^(P))₃ or optionally substituted C₁₋₆aliphatic; wherein each R^(P) is independently C₁₋₆ aliphatic or phenyl.In some embodiments, R^(e) is —Si(R^(P))₃. In some embodiments, R^(e) isoptionally substituted C₁₋₆ aliphatic. In some embodiments, R^(e) isoptionally substituted C₁₋₆ alkyl. In some embodiments, R^(e) ist-butyl. In some embodiments, R^(e) is benzyl. In some embodiments,R^(e) is benzhydryl. In some embodiments, R^(e) is trityl.

In some embodiments, step S-1 comprises the alkylation of intermediateG-2 by intermediate G-1, thereby forming intermediate G-3. One ofordinary skill will appreciate that a variety of leaving groups R^(H)are suitable to effect the alkylation of G-2. In some embodiments, thealkylation is mediated by a base. In some embodiments, the base is analkoxide base. In some embodiments, the base is an alkali metalalkoxide. In some embodiments, the base is potassium t-butoxide. In someembodiments, the base is sodium t-butoxide. In some embodiments, thebase is potassium t-amyloxide. In some embodiments, the base is acarbonate base. In some embodiments, the carbonate base is an alkalimetal carbonate. In some embodiments, the alkali metal carbonate ispotassium carbonate or cesium carbonate. In some embodiments, the alkalimetal carbonate is potassium carbonate, potassium bicarbonate, cesiumcarbonate, or cesium bicarbonate. In some embodiments, the alkali metalcarbonate is potassium carbonate. In some embodiments, the alkali metalcarbonate is potassium carbonate or potassium bicarbonate. In someembodiments, the alkali metal carbonate is cesium carbonate. In someembodiments, the alkali metal carbonate is cesium carbonate or cesiumbicarbonate. In some embodiments, step S-1 proceeds in a polar solvent.In some embodiments, the polar solvent is a polar aprotic solvent. Insome embodiments, the polar aprotic solvent is N-methylpyrrolidone(NMP). In some embodiments, the polar aprotic solvent isdimethylformamide (DMF). In some embodiments, the polar aprotic solventis dimethylacetamide (DMA). In some embodiments, crystallineintermediate G-3 is purified by crystallization.

In some embodiments, step S-2 comprises the coupling of intermediate G-3with an oxazole synthon (oxazole), thereby forming intermediate G-4. Insome embodiments, the coupling is a metal-catalyzed coupling. In someembodiments, the metal-catalyzed coupling is a Negishi coupling. One ofskill in the art will appreciate that a Negishi coupling is a transitionmetal-catalyzed cross-coupling of an organic halide or sulfonatecompound with an organozinc compound. In some embodiments, the oxazolesynthon is an oxazole zincate. In some embodiments, the oxazole zincateis formed by metal exchange between 2-lithio-oxazole and a zinc salt. Insome embodiments the zinc salt is ZnCl₂. In some embodiments, the2-lithio-oxazole is formed by treating oxazole with n-butyllithium. Insome embodiments, the 2-lithio-oxazole is formed at a temperature below−40° C. In some embodiments, the 2-lithio-oxazole is formed at atemperature below about −40° C. In some embodiments, the2-lithio-oxazole is formed at a temperature below −60° C. In someembodiments, the 2-lithio-oxazole is formed at a temperature below about−60° C. In some embodiments, the metal catalyst is a palladium catalyst.In some embodiments, the palladium catalyst is Pd(PPh₃)₄. In someembodiments, crystalline intermediate G-4 is purified bycrystallization.

In some embodiments, the oxazole is treated with a metalating agentselected from isopropyl magnesium chloride, isopropyl magnesium bromide,TMPZnCl—LiCl, TMPMgCl—LiCl, and isopropyl magnesium chloride/lithiumchloride (wherein TMP refers to 2,2,6,6,-tetramethylpiperidine). In someembodiments, the metalating agent is isopropyl magnesium chloride. Insome embodiments, the oxazole is treated with isopropyl magnesiumchloride (2 M in THF). In some embodiments, the oxazole is treated witha metalating agent at about −20° C. to about −10° C. In someembodiments, the oxazole is treated with a metalating agent at about−15° C. In some embodiments, the solvent is tetrahydrofuran,2-methyltetrahydrofuran, or a mixture thereof. In some embodiments, thesolvent is tetrahydrofuran and 2-methyltetrahydrofuran. In someembodiments, the reaction further comprises adding ZnCl₂ to form anoxazole zincate. In some embodiments, the reaction further comprisesadding ZnCl₂ as a solution in 2-methyltetrahydrofuran. In someembodiments, the catalyst used in the Negishi coupling is a palladiumcatalyst selected from Pd(PPh₃)₄, tBuXPhos Pd precatalyst, XPhos Pdprecatalyst, RuPhos Pd precatalyst, and Pd-PEPPSI-IPent(dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)).Such precatalysts are described in, for example, Bruneau et al., ACSCatal., 2015, 5(2), pp. 1386-1396. In some embodiments, the catalyst isPd(PPh₃)₄. In some embodiments, the reaction mixture is heated togreater than about 50° C. after addition of ZnCl₂. In some embodiments,the reaction mixture is heated to about 65° C.

In some embodiments, step S-3 comprises the deprotection of esterintermediate G-4 to provide a compound of formula I. In someembodiments, where R^(e) is benzyl or benzhydryl, the deprotection is acatalytic hydrogenation using a hydrogen source. In some embodiments,the catalyst is a palladium catalyst. In some embodiments, the palladiumcatalyst is palladium on carbon. In some embodiments, the hydrogensource is H₂. In some embodiments, residual hydrogen catalyst is removedby means of a palladium scavenger. In some embodiments, the palladiumscavenger is a thiol. In some embodiments, the thiol is SiliaMetS thiol.In some embodiments, the deprotection is a hydrolysis reaction. In someembodiments, the hydrolysis is an acidic hydrolysis. In someembodiments, the acid is a strong, protic acid. In some embodiments, theacid is sulfuric acid. In some embodiments, the acid is sulfuric acid,tetrafluoroboric acid, methanesulfonic acid, nitric acid, orhydrochloric acid. In some embodiments, the reaction occurs in aco-solvent, wherein the co-solvent is an alcohol. In some embodiments,the co-solvent is 2-propanol, t-butanol, t-amyl alcohol, or ethanol. Insome embodiments, the co-solvent is 2-propanol, t-butanol, t-amylalcohol, ethanol, or acetonitrile.

In some embodiments, the temperature of the hydrolysis reaction ismaintained between 5 and 10° C. In some embodiments, the temperature ofthe hydrolysis reaction is between about 0 and about 20° C. In someembodiments, the temperature of the hydrolysis reaction is between about2 and about 8° C. In some embodiments, the temperature of the hydrolysisreaction is maintained between about 2 and about 10° C. In someembodiments, the product is purified by crystallization. In someembodiments, the product is crystallized from an alcohol solution. Insome embodiments, the alcohol solution is a mixture of ethanol andwater. In some embodiments, the product is crystallized from a mixtureof acetonitrile and water.

In some embodiments, intermediates of formula G-1 are prepared accordingto the method depicted in Scheme 2, wherein each of R^(a), R^(H), R², R⁵are as defined in classes and subclasses herein, both singly and incombination.

In some embodiments, step S-4 comprises the conversion of the hydroxylgroup of intermediate G-5 to a leaving group, R^(H). In someembodiments, intermediate G-5 is an alcohol or an oxygen anion thereof.In some embodiments, where R^(H) is a sulfonate group, G-5 is treatedwith a sulfonylating reagent. In some embodiments, the sulfonate groupis a mesylate, a triflate, a benzenesulfonate, a tosylate, a brosylate,or a nosylate. In some embodiments, the sulfonylating reagent is asulfonyl halide. In some embodiments the sulfonylating reagent is asulfonyl chloride. In some embodiments the sulfonyl chloride ismethanesulfonyl chloride.

In some embodiments, where R^(H) is a halogen, the hydroxyl group isconverted directly to a halogen by means of a halogenating reagent. Insome embodiments, the halogenating reagent is a brominating reagent.

In some embodiments, where R^(H) is a halogen, the hydroxyl group isfirst converted to a first leaving group, and then that first leavinggroup is further converted to the halogen. In some embodiments, thefirst leaving group is a sulfonate. In some embodiments, the sulfonateis a mesylate, a triflate, a benzenesulfonate, a tosylate, a brosylate,or a nosylate. In some embodiments, the sulfonate is a methanesulfonate.In some embodiments, the methanesulfonylate is formed by treatment ofG-5 with methanesulfonyl chloride. In some embodiments, the sulfonate isformed in the presence of a base. In some embodiments, the base is anamine base. In some embodiments, the amine base is triethylamine,diisopropylethylamine (Hunig's base),1,8-diazabicyclo[5.4.0]undec-7-ene, pyridine, or dimethylaminopyridine(DMAP). In some embodiments, the amine base is trimethylamine. In someembodiments, the amine base is triethylamine. In some embodiments, thesolvent is 2-methyltetrahydrofuran, tetrahydrofuran, or dichloromethane.In some embodiments, the solvent is 2-methyltetrahydrofuran. In someembodiments, the reaction further comprises a promoter. In someembodiments, the promoter is NaI or tetrabutylammonium iodide. In someembodiments, the reaction takes place at about 20° C. to about 30° C. Insome embodiments, the reaction takes place at about 22° C.

In some embodiments, the first leaving group is further converted to ahalogen by displacement with halide. In some embodiments, the halide isbromide. In some embodiments, the source of halide is a metal halide. Insome embodiments, the source of bromide is a metal bromide. In someembodiments, the metal bromide is an alkali metal bromide. In someembodiments, the alkali metal bromide is LiBr. In some embodiments, thealkali metal bromide is NaBr. In some embodiments, the alkali metalbromide is KBr. In some embodiments, this displacement further comprisesa promoter. In some embodiments, the promoter is a phase transfercatalyst. The promoter can include, but is not limited totetramethylammonium bromide or tetrabutylammonium bromide. In someembodiments, the displacement takes place in a polar solvent. In someembodiments, the polar solvent is a polar aprotic solvent. In someembodiments, the polar aprotic solvent is N-methylpyrrolidone (NMP). Insome embodiments, the polar aprotic solvent is dimethylformamide (DMF).In some embodiments, the polar aprotic solvent is dimethylacetamide(DMAc). In some embodiments, the polar aprotic solvent is ethyl acetate(EtOAc). In some embodiments, the reaction takes place at about 50° C.to about 60° C. In some embodiments, the reaction takes place at about55° C. In some embodiments, leaving group formation step S-4 andalkylation step S-1 are performed together without the isolation ofintermediate G-1.

In some embodiments, intermediates of formula G-5 are prepared accordingto the method depicted in Scheme 3, wherein each of R^(a), R², R⁵ are asdefined in classes and subclasses herein, both singly and incombination.

In some embodiments, step S-5 comprises the epoxidation of aldehyde G-6,thereby forming the epoxide of formula rac-G-7. In some embodiments, theepoxidation is a Corey-Chaykovsky epoxidation. One of skill in the artwill appreciate that a Corey-Chaykovsky epoxidation is the use of asulfur ylide to convert a carbonyl compound to its correspondingepoxide. In some embodiments, the sulfur ylide is formed from atrimethylsulfonium or trimethylsulfoxonium salt. In some embodiments,the sulfur ylide is formed from trimethylsulfoxonium iodide. In someembodiments, the sulfur ylide is formed from trimethylsulfoxoniummesylate.

In some embodiments, step S-6 comprises epoxide opening of intermediaterac-G-7 by an alcohol of formula R^(a)—OH, wherein R^(a) is as definedin classes and subclasses herein, thereby forming intermediate rac-G-5.In some embodiments, the epoxide opening is acid catalyzed. In someembodiments, the acid is a Lewis acid. In some embodiments, the Lewisacid is a metal halide or metal sulfonate. In some embodiments, theLewis acid is an iron salt. In some embodiments, the Lewis acid isFeCl₃. In some embodiments, step S-6 is conducted without additionalsolvent. In some embodiments, the Lewis acid is BF₃-Et₂O. In someembodiments, the solvent of step S-6 is toluene. In some embodiments,the acid is HBF₄—OEt₂, HBF₄-water, or camphorsulfonic acid. In someembodiments, the solvent of step S-6 is dichloromethane.

In some embodiments, step S-7 comprises the selective acylation of the(R)-isomer of intermediate G-5, with an [acyl] donor, thereby producingintermediate (R)-G-8 and residual (S)-G-5. In some embodiments, the[acyl] donor is of the formula R^(x)C(O)OR^(y), wherein R^(x) isoptionally substituted C₁₋₄ aliphatic; and R^(y) is optionallysubstituted C₁₋₄ aliphatic or optionally substituted C₁₋₄ acyl. In someembodiments, the [acyl] donor provides a C₄-acyl group. In someembodiments, the [acyl] donor is an optionally substituted 4-7 memberedlactone or an optionally substituted 4-7 membered cyclic anhydride. Insome embodiments, the [acyl] donor is an optionally substituted 4-7membered cyclic anhydride. In some embodiments, the [acyl] donor isvinyl acetate, and [acyl] is acetyl. In some embodiments, the [acyl]donor is vinyl butyrate, and [acyl] is butyryl. In some embodiments, the[acyl] donor is succinic anhydride, and [acyl] is succinyl.

In some embodiments, the acylation is a kinetic resolution. In someembodiments the kinetic resolution is accomplished by a lipase enzyme.In some embodiments, the lipase enzyme is Candida antarctica lipase B(CAL-B). In some embodiments, the lipase enzyme is Novozyme 435. In someembodiments, the acylation reaction is conducted in THF solvent. In someembodiments, the acylation reaction is conducted in toluene solvent. Insome embodiments, the acylation reaction is conducted in a mixture ofTHF and toluene. In some embodiments, when [acyl] is succinyl, unreactedintermediate G-5 is separated from (R)-G-8 by forming the succinateanion under aqueous basic conditions and extracting the unreactedneutral alcohol species into an organic solvent.

In some embodiments, step S-8 comprises the hydrolysis ofenantiomerically enriched intermediate (R)-G-8, thereby forming (R)-G-5.In some embodiments, the hydrolysis is an aqueous hydrolysis. In someembodiments, the aqueous hydrolysis is an alkaline hydrolysis. In someembodiments, the aqueous hydrolysis is mediated by hydroxide. In someembodiments, the aqueous hydrolysis is mediated by sodium hydroxide. Insome embodiments, steps S-7 and S-8 are performed without the isolationof intermediate (R)-G-8.

In some embodiments, the (R)-G-8 produced has an enantiomeric excess ofgreater than 70%, 80%, 90%, 95%, 97%, 98%, 99%, or 99.5%.

In some embodiments, compounds of formula G-4 are prepared according tothe method depicted in Scheme 4, wherein each of R^(a), R^(e), R^(H),R², R⁵ are as defined in classes and subclasses herein, both singly andin combination.

In some embodiments, step S-9 comprises the alkylation of intermediateG-9 by alkyl halide G-1, thereby forming intermediate G-4. In someembodiments, the alkylation is mediated by a base. In some embodiments,the base is an alkoxide base. In some embodiments, the base is an alkalimetal alkoxide. In some embodiments, the base is potassium t-butoxide.In some embodiments, the base is sodium t-butoxide. In some embodiments,the base is potassium t-amyloxide. In some embodiments, the base is acarbonate base. In some embodiments, the carbonate base is an alkalimetal carbonate. In some embodiments, the alkali metal carbonate issodium carbonate, sodium bicarbonate, potassium carbonate, potassiumbicarbonate, cesium carbonate, cesium bicarbonate, potassium phosphatetribasic, or potassium phosphate dibasic. In some embodiments, thealkali metal carbonate is potassium carbonate or cesium carbonate. Insome embodiments, the alkali metal carbonate is potassium carbonate. Insome embodiments, the alkali metal carbonate is potassium bicarbonate.In some embodiments, the alkali metal carbonate is cesium bicarbonate.In some embodiments, step S-9 proceeds in a polar solvent. In someembodiments, the polar solvent is a polar aprotic solvent. In someembodiments, the polar aprotic solvent is N-methylpyrrolidone (NMP). Insome embodiments, the polar aprotic solvent is dimethylformamide (DMF).In some embodiments, the polar aprotic solvent is dimethylacetamide(DMA). In some embodiments, the reaction takes place at a temperature ofabout 90° C. to about 100° C. In some embodiments, the reaction takesplace at a temperature of about 100° C. to about 140° C. In someembodiments, the reaction takes place at a temperature of about 115° C.

In some embodiments, compounds of formula G-2 and G-9 are preparedaccording to the method depicted in Scheme 5, wherein R^(e) is asdefined in classes and subclasses herein.

In some embodiments, step S-10 comprises a urea formation betweenintermediates G-10 (or a salt thereof), and G-11 (or a salt thereof),thereby forming the intermediate of formula G-12. In some embodiments,the urea formation proceed using a carbonyl source. In some embodiments,the carbonyl source is carbonyldiimidazole (CDI). In some embodiments,the carbonyl source is triphosgene. In some embodiments, theintermediate of formula G-11 is used as its hydrochloride salt. In someembodiments, an additional base is used. In some embodiments, the baseis an amine base. In some embodiments, the amine base is triethylamine.

In some embodiments, step S-11 comprises the bromination of anintermediate of formula G-12, thereby forming an intermediate of formulaG-13. In some embodiments, the brominating reagent isN-bromosuccinimide. In some embodiments, the bromination is conducted ina polar aprotic solvent. In some embodiments, the polar aprotic solventis dimethylformamide (DMF).

In some embodiments, step S-12 comprises the intramolecular cyclizationof an intermediate of formula G-13, thereby forming an intermediate offormula G-2. In some embodiments, the intramolecular cyclization iseffected by a strong base. In some embodiments, the strong base is analkali metal alkoxide. In some embodiments, the alkali metal alkoxide ispotassium t-butoxide. In some embodiments, the intramolecularcyclization is conducted in an ether solvent. In some embodiments, theether solvent is 1,4-dioxane.

In some embodiments, step S-13 comprises the coupling of intermediateG-2 with an oxazole synthon (oxazole or oxazole metallate), therebyforming intermediate G-9. In some embodiments, the coupling is ametal-catalyzed coupling. In some embodiments, the metal-catalyzedcoupling is a Negishi coupling. One of skill in the art will appreciatethat a Negishi coupling is a transition metal-catalyzed cross-couplingof an organic halide or sulfonate compound with an organozinc compound.In some embodiments, the oxazole synthon is an oxazole zincate. In someembodiments, the oxazole zincate is formed by metal exchange between2-lithio-oxazole and a zinc salt. In some embodiments the zinc salt isZnCl₂. In some embodiments, the 2-lithio-oxazole is formed by treatingoxazole with n-butyllithium. In some embodiments, the 2-lithio-oxazoleis formed at a temperature below −40° C. In some embodiments, the2-lithio-oxazole is formed at a temperature below −60° C. In someembodiments, the transition metal catalyst is a palladium catalyst. Insome embodiments, the palladium catalyst is Pd(PPh₃)₄. In someembodiments, crystalline intermediate G-4 is purified bycrystallization.

In some embodiments, the oxazole is treated with a metalating agentselected from isopropyl magnesium chloride, isopropyl magnesium bromide,TMPZnCl—LiCl, TMPMgCl—LiCl, and isopropyl magnesium chloride/lithiumchloride (wherein TMP refers to 2,2,6,6,-tetramethylpiperidine). In someembodiments, the metalating agent is isopropyl magnesium chloride. Insome embodiments, the oxazole is treated with isopropyl magnesiumchloride (2 M in THF). In some embodiments, the oxazole is treated witha metalating agent at about −20° C. to about −10° C. In someembodiments, the oxazole is treated with a metalating agent at about−15° C. In some embodiments, the solvent is tetrahydrofuran,2-methyltetrahydrofuran, or a mixture thereof. In some embodiments, thesolvent is tetrahydrofuran and 2-methyltetrahydrofuran. In someembodiments, the reaction further comprises adding ZnCl₂ to form anoxazole zincate. In some embodiments, the reaction further comprisesadding ZnCl₂ as a solution in 2-methyltetrahydrofuran. In someembodiments, the catalyst used in the Negishi coupling is a palladiumcatalyst selected from Pd(PPh₃)₄, tBuXPhos Pd precatalyst, XPhos Pdprecatalyst, RuPhos Pd precatalyst, and Pd-PEPPSI-IPent(dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)).Such precatalysts are described in, for example, Bruneau et al., ACSCatal., 2015, 5(2), pp. 1386-1396. In some embodiments, the catalyst isPd(PPh₃)₄. In some embodiments, the reaction mixture is heated togreater than about 50° C. after addition of ZnCl₂. In some embodiments,the reaction mixture is heated to about 65° C.

In some embodiments, step S-11 comprises the chlorination of anintermediate of formula G-12, thereby forming an intermediate of formulaG-13-a. In some embodiments, the chlorinating reagent isN-chlorosuccinimide. In some embodiments, G-13-a can be used in stepS-12 in place of G-13 as described above to form the chloro analog ofG-2, which can be used in step S-13 in place of G-2.

Some embodiments provide for a process for preparing Compound 1:

comprising contacting compound G-4-a:

with acid.

Some embodiments provide for a process for preparing compound G-4-a:

comprising contacting compound G-9-a:

with a compound of the formula H-1:

wherein R^(H) is halogen.

In some embodiments, R^(H) is bromo.

Some embodiments provide for a process for preparing Compound 1:

comprising contacting a compound of the formula G-4-b:

with a hydrogen source and a palladium catalyst.

Some embodiments provide for a process for preparing an enantiomericallyenriched compound of formula (R)-G-5:

wherein R^(a) is an optionally substituted group selected from a 3-7membered ring having 0-2 heteroatoms selected from nitrogen, oxygen, andsulfur, and C₁₋₆ aliphatic;

-   R² is hydrogen, or optionally substituted C₁₋₆ aliphatic; and-   R⁵ is hydrogen or halogen;-   comprising the steps of:    -   a) contacting a racemic compound of formula rac-G-5:

with a lipase enzyme and an [acyl] donor, thereby forming a compound offormula (R)-G-8:

wherein [acyl] is a C₁-C₇ acyl group; and

-   -   b) removing the [acyl] group;

-   thereby preparing the enantiomerically enriched compound of formula    (R)-G-5.

In some embodiments, the compound of formula (R)-G-5 is:

In some embodiments, the [acyl] donor is an optionally substituted 4-7membered lactone or 4-7 membered optionally substituted cyclicanhydride; or a compound of the formula R^(x)C(O)OR^(y), wherein R^(x)is optionally substituted C₁₋₄ aliphatic; and R^(y) is optionallysubstituted C₁₋₄ aliphatic or optionally substituted C₁₋₄ acyl.

In some embodiments, the [acyl] is a C₄ acyl group.

In some embodiments, the lipase enzyme is Candida antarctica lipase B.

Some embodiments provide for a process of preparing a compound G-9-a:

contacting compound G-2-a:

with oxazole under conditions sufficient to form compound G-9-a.

In some embodiments, the reaction conditions comprise a solvent, whereinthe solvent is tetrahydrofuran, 2-methyltetrahydrofuran, or a mixturethereof. In some embodiments, the solvent is tetrahydrofuran and2-methyltetrahydrofuran.

In some embodiments, the reaction conditions comprise a metalatingagent. In some embodiments, the metalating agent selected from isopropylmagnesium chloride, isopropyl magnesium bromide, TMPZnCl—LiCl,TMPMgCl—LiCl, and isopropyl magnesium chloride/lithium chloride (whereinTMP refers to 2,2,6,6,-tetramethylpiperidine). In some embodiments, themetalating agent is isopropyl magnesium chloride. In some embodiments,the reaction conditions comprise contacting the oxazole and metalatingagent at about −20° C. to −10° C. or about −15° C.

In some embodiments, the reaction conditions comprise adding ZnCl₂. Insome embodiments, the catalyst is a palladium catalyst selected fromPd(PPh₃)₄, tBuXPhos Pd precatalyst, XPhos Pd precatalyst, RuPhos Pdprecatalyst, and Pd-PEPPSI-IPent(dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)).In some embodiments, the catalyst is Pd(PPh₃)₄. In some embodiments, thereaction mixture is heated to greater than about 50° C. after additionof ZnCl₂. In some embodiments, the reaction mixture is heated to about60° C. to about 70° C. after addition of ZnCl₂.

Some embodiments provide for a process of preparing a compound(R)-G-1-a:

comprising:

-   (a) contacting compound (R)-G-5-a or an oxygen anion thereof:

with a sulfonylating reagent under conditions sufficient to formcompound (R)-G-6-a:

(b) contacting compound (R)-G-6-a with a bromide salt under conditionssufficient to form compound (R)-G-1-a.

In some embodiments, the sulfonylating reagent is methanesulfonylchloride.

In some embodiments, the reaction conditions of step (a) comprise abase. In some embodiments, the base is triethylamine,diisopropylethylamine (Hunig's base),1,8-diazabicyclo[5.4.0]undec-7-ene, pyridine, or dimethylaminopyridine(DMAP). In some embodiments, the base is triethylamine. In someembodiments, the reaction conditions of step (a) comprise a solventselected from 2-methyltetrahydrofuran, tetrahydrofuran, anddichloromethane. In some embodiments, the solvent is2-methyltetrahydrofuran. In some embodiments, the reaction conditions ofstep (a) comprise a promoter. In some embodiments, the promoter is NaIor tetrabutylammonium iodide. In some embodiments, the reactionconditions of step (a) comprise a temperature of about 20° C. to about30° C. In some embodiments, the reaction conditions of step (a) comprisea temperature of about 22° C.

In some embodiments, the bromide salt is LiBr, NaBr, or KBr. In someembodiments, the bromide salt is LiBr. In some embodiments, the bromidesalt is an ammonium salt. In some embodiments, the bromide salt istetrabutylammonium bromide.

In some embodiments, the reaction conditions of step (b) comprise asolvent selected from N-methylpyrrolidone (NMP), dimethylformamide(DMF), and dimethylacetamide (DMAc). In some embodiments, the solvent isNMP. In some embodiments, In some embodiments, the reaction conditionsof step (b) comprise a temperature of about 50° C. to about 60° C. Insome embodiments, In some embodiments, the reaction conditions of step(b) comprise a temperature of about 55° C.

Some embodiments provide for a process of preparing Compound 1:

or salt or co-crystal thereof, comprising:

-   (a) contacting compound G-2-a:

with oxazole under conditions sufficient to form compound G-9-a:

(b) contacting compound G-9-a with compound (R)-G-1-a:

under conditions sufficient to form a compound G-4-a:

and (c) hydrolyzing compound G-4-a under conditions sufficient to formCompound 1.

In some embodiments, the reaction conditions of step (a) comprise asolvent, wherein the solvent is tetrahydrofuran,2-methyltetrahydrofuran, or a mixture thereof. In some embodiments, thesolvent is tetrahydrofuran and 2-methyltetrahydrofuran.

In some embodiments, the reaction conditions of step (a) comprise ametalating agent. In some embodiments, the metalating agent selectedfrom isopropyl magnesium chloride, isopropyl magnesium bromide,TMPZnCl—LiCl, TMPMgCl—LiCl, and isopropyl magnesium chloride/lithiumchloride (wherein TMP refers to 2,2,6,6,-tetramethylpiperidine). In someembodiments, the metalating agent is isopropyl magnesium chloride. Insome embodiments, the reaction conditions of step (a) comprisecontacting the oxazole and metalating agent at about −20° C. to −10° C.or about −15° C.

In some embodiments, the reaction conditions of step (a) comprise addingZnCl₂. In some embodiments, the catalyst is a palladium catalystselected from Pd(PPh₃)₄, tBuXPhos Pd precatalyst, XPhos Pd precatalyst,RuPhos Pd precatalyst, and Pd-PEPPSI-IPent. In some embodiments, thecatalyst is Pd(PPh₃)₄. In some embodiments, the reaction mixture isheated to greater than about 50° C. after addition of ZnCl₂. In someembodiments, the reaction mixture is heated to about 60° C. to about 70°C. after addition of ZnCl₂.

In some embodiments, the reaction conditions of step (b) comprise abase. In some embodiments, the base is sodium carbonate, sodiumbicarbonate, potassium carbonate, potassium bicarbonate, cesiumcarbonate, cesium bicarbonate, potassium phosphate tribasic, orpotassium phosphate dibasic. In some embodiments, the base is sodiumcarbonate, sodium bicarbonate, potassium carbonate, potassiumbicarbonate, cesium carbonate, or cesium bicarbonate. In someembodiments, the base is potassium carbonate. In some embodiments, thebase is potassium carbonate or potassium bicarbonate.

In some embodiments, the reaction conditions of step (b) comprise asolvent selected from N-methylpyrrolidone (NMP), dimethylformamide(DMF), and dimethylacetamide (DMA). In some embodiments, the solvent isNMP.

In some embodiments, the reaction conditions of step (b) comprise atemperature of about 100° C. to about 140° C. In some embodiments, thereaction conditions of step (b) comprise a temperature of about 115° C.

In some embodiments, the reaction conditions of step (c) comprise anacid. In some embodiments, the acid is sulfuric acid, tetrafluoroboricacid, methanesulfonic acid, nitric acid, or hydrochloric acid. In someembodiments, the acid is sulfuric acid. In some embodiments, the acid ishydrochloric acid.

In some embodiments, the reaction conditions of step (c) comprise aco-solvent. In some embodiments, the co-solvent is an alcohol. In someembodiments, the co-solvent is 2-propanol, t-butanol, t-amyl alcohol,ethanol, or acetonitrile.

In some embodiments, the reaction conditions of step (c) comprise atemperature of about 5 and 10° C. In some embodiments, the reactionconditions of step (c) comprise a temperature between about 0 and about20° C. In some embodiments, the reaction conditions of step (c) comprisebetween about 2 and about 8° C.

Some embodiments provide for a process of preparing Compound 1:

or a salt or co-crystal thereof, comprising:

-   (a) contacting compound (R)-G-6-a:

with a bromide salt under conditions sufficient to form compound(R)-G-1-a:

(b) contacting compound G-2-a:

with oxazole under conditions sufficient to form compound G-9-a:

(c) contacting compound G-9-a with compound (R)-G-1-a under conditionssufficient to form a compound G-4-a:

and (d) hydrolyzing compound G-4-a under conditions sufficient to formCompound 1.

In some embodiments, the bromide salt is LiBr, NaBr, or KBr. In someembodiments, the bromide salt is LiBr. In some embodiments, the bromidesalt is an ammonium salt. In some embodiments, the bromide salt istetrabutylammonium bromide.

In some embodiments, the reaction conditions of step (a) comprise asolvent selected from N-methylpyrrolidone (NMP), dimethylformamide(DMF), and dimethylacetamide (DMAc). In some embodiments, the solvent isNMP. In some embodiments, In some embodiments, the reaction conditionsof step (a) comprise a temperature of about 50° C. to about 60° C. Insome embodiments, In some embodiments, the reaction conditions of step(a) comprise a temperature of about 55° C.

In some embodiments, the bromide salt is LiBr, NaBr, or KBr. In someembodiments, the bromide salt is LiBr. In some embodiments, the bromidesalt is an ammonium salt. In some embodiments, the bromide salt istetrabutylammonium bromide.

In some embodiments, the reaction conditions of step (b) comprise asolvent, wherein the solvent is tetrahydrofuran,2-methyltetrahydrofuran, or a mixture thereof. In some embodiments, thesolvent is tetrahydrofuran and 2-methyltetrahydrofuran.

In some embodiments, the reaction conditions of step (b) comprise ametalating agent. In some embodiments, the metalating agent selectedfrom isopropyl magnesium chloride, isopropyl magnesium bromide,TMPZnCl—LiCl, TMPMgCl—LiCl, and isopropyl magnesium chloride/lithiumchloride (wherein TMP refers to 2,2,6,6,-tetramethylpiperidine). In someembodiments, the metalating agent is isopropyl magnesium chloride. Insome embodiments, the reaction conditions of step (b) comprisecontacting the oxazole and metalating agent at about −20° C. to −10° C.or about −15° C.

In some embodiments, the reaction conditions of step (b) comprise addingZnCl₂. In some embodiments, the catalyst is a palladium catalystselected from Pd(PPh₃)₄, tBuXPhos Pd precatalyst, XPhos Pd precatalyst,RuPhos Pd precatalyst, and Pd-PEPPSI-IPent. In some embodiments, thecatalyst is Pd(PPh₃)₄. In some embodiments, the reaction mixture isheated to greater than about 50° C. after addition of ZnCl₂. In someembodiments, the reaction mixture is heated to about 60° C. to about 70°C. after addition of ZnCl₂.

In some embodiments, the reaction conditions of step (c) comprise abase. In some embodiments, the base is sodium carbonate, sodiumbicarbonate, potassium carbonate, potassium bicarbonate, cesiumcarbonate, cesium bicarbonate, potassium phosphate tribasic, orpotassium phosphate dibasic. In some embodiments, the base is sodiumcarbonate, sodium bicarbonate, potassium carbonate, potassiumbicarbonate, cesium carbonate, cesium bicarbonate, potassium phosphatetribasic, or potassium phosphate dibasic. In some embodiments, the baseis sodium carbonate, sodium bicarbonate, potassium carbonate, potassiumbicarbonate, cesium carbonate, or cesium bicarbonate. In someembodiments, the base is potassium carbonate. In some embodiments, thebase is potassium carbonate or potassium bicarbonate.

In some embodiments, the reaction conditions of step (c) comprise asolvent selected from N-methylpyrrolidone (NMP), dimethylformamide(DMF), and dimethylacetamide (DMA). In some embodiments, the solvent isNMP.

In some embodiments, the reaction conditions of step (c) comprise atemperature of about 90° C. to about 100° C. In some embodiments, thereaction conditions of step (c) comprise a temperature of about 100° C.to about 140° C. In some embodiments, the reaction conditions of step(c) comprise a temperature of about 115° C.

In some embodiments, the reaction conditions of step (d) comprise anacid. In some embodiments, the acid is sulfuric acid, tetrafluoroboricacid, methanesulfonic acid, nitric acid, or hydrochloric acid. In someembodiments, the acid is sulfuric acid. In some embodiments, the acid ishydrochloric acid.

In some embodiments, the reaction conditions of step (d) comprise aco-solvent. In some embodiments, the co-solvent is an alcohol. In someembodiments, the co-solvent is 2-propanol, t-butanol, t-amyl alcohol,ethanol, or acetonitrile.

In some embodiments, the reaction conditions of step (d) comprise atemperature of about 5 and 10° C. In some embodiments, the reactionconditions of step (d) comprise a temperature between about 0 and about20° C. In some embodiments, the reaction conditions of step (e) comprisebetween about 2 and about 8° C.

Some embodiments provide for a process of preparing Compound 1:

or salt or co-crystal thereof, comprising:

-   (a) contacting compound (R)-G-5-a or an oxygen anion thereof:

with a sulfonylating reagent under conditions sufficient to formcompound (R)-G-6-a:

(b) contacting compound (R)-G-6-a with a bromide salt under conditionssufficient to form compound (R)-G-1-a:

(c) contacting compound G-2-a:

with oxazole under conditions sufficient to form compound G-9-a:

(d) contacting compound G-9-a with compound (R)-G-1-a under conditionssufficient to form a compound G-4-a:

and (e) hydrolyzing compound G-4-a under conditions sufficient to formCompound 1.

In some embodiments, the sulfonylating reagent is methanesulfonylchloride.

In some embodiments, the reaction conditions of step (a) comprise abase. In some embodiments, the base is triethylamine,diisopropylethylamine (Hunig's base),1,8-diazabicyclo[5.4.0]undec-7-ene, pyridine, or dimethylaminopyridine(DMAP). In some embodiments, the base is triethylamine. In someembodiments, the reaction conditions of step (a) comprise a solventselected from 2-methyltetrahydrofuran, tetrahydrofuran, anddichloromethane. In some embodiments, the solvent is2-methyltetrahydrofuran. In some embodiments, the reaction conditions ofstep (a) comprise a promoter. In some embodiments, the promoter is NaIor tetrabutylammonium iodide. In some embodiments, the reactionconditions of step (a) comprise a temperature of about 20° C. to about30° C. In some embodiments, the reaction conditions of step (a) comprisea temperature of about 22° C.

In some embodiments, the bromide salt is LiBr, NaBr, or KBr. In someembodiments, the bromide salt is LiBr. In some embodiments, the bromidesalt is an ammonium salt. In some embodiments, the bromide salt istetrabutylammonium bromide.

In some embodiments, the reaction conditions of step (b) comprise asolvent selected from N-methylpyrrolidone (NMP), dimethylformamide(DMF), and dimethylacetamide (DMAc). In some embodiments, the solvent isNMP. In some embodiments, In some embodiments, the reaction conditionsof step (b) comprise a temperature of about 50° C. to about 60° C. Insome embodiments, In some embodiments, the reaction conditions of step(b) comprise a temperature of about 55° C.

In some embodiments, the reaction conditions of step (c) comprise asolvent, wherein the solvent is tetrahydrofuran,2-methyltetrahydrofuran, or a mixture thereof. In some embodiments, thesolvent is tetrahydrofuran and 2-methyltetrahydrofuran.

In some embodiments, the reaction conditions of step (c) comprise ametalating agent. In some embodiments, the metalating agent selectedfrom isopropyl magnesium chloride, isopropyl magnesium bromide,TMPZnCl—LiCl, TMPMgCl—LiCl, and isopropyl magnesium chloride/lithiumchloride (wherein TMP refers to 2,2,6,6,-tetramethylpiperidine). In someembodiments, the metalating agent is isopropyl magnesium chloride. Insome embodiments, the reaction conditions of step (c) comprisecontacting the oxazole and metalating agent at about −20° C. to −10° C.or about −15° C.

In some embodiments, the reaction conditions of step (c) comprise addingZnCl₂. In some embodiments, the catalyst is a palladium catalystselected from Pd(PPh₃)₄, tBuXPhos Pd precatalyst, XPhos Pd precatalyst,RuPhos Pd precatalyst, and Pd-PEPPSI-IPent. In some embodiments, thecatalyst is Pd(PPh₃)₄. In some embodiments, the reaction mixture isheated to greater than about 50° C. after addition of ZnCl₂. In someembodiments, the reaction mixture is heated to about 60° C. to about 70°C. after addition of ZnCl₂.

In some embodiments, the reaction conditions of step (d) comprise abase. In some embodiments, the base is sodium carbonate, sodiumbicarbonate, potassium carbonate, potassium bicarbonate, cesiumcarbonate, cesium bicarbonate, potassium phosphate tribasic, orpotassium phosphate dibasic. In some embodiments, the base is sodiumcarbonate, sodium bicarbonate, potassium carbonate, potassiumbicarbonate, cesium carbonate, cesium bicarbonate, potassium phosphatetribasic, or potassium phosphate dibasic. In some embodiments, the baseis sodium carbonate, sodium bicarbonate, potassium carbonate, potassiumbicarbonate, cesium carbonate, or cesium bicarbonate. In someembodiments, the base is potassium carbonate. In some embodiments, thebase is potassium carbonate or potassium bicarbonate.

In some embodiments, the reaction conditions of step (d) comprise asolvent selected from N-methylpyrrolidone (NMP), dimethylformamide(DMF), and dimethylacetamide (DMA). In some embodiments, the solvent isNMP.

In some embodiments, the reaction conditions of step (d) comprise atemperature of about 90° C. to about 100° C. In some embodiments, thereaction conditions of step (d) comprise a temperature of about 100° C.to about 140° C. In some embodiments, the reaction conditions of step(d) comprise a temperature of about 115° C.

In some embodiments, the reaction conditions of step (e) comprise anacid. In some embodiments, the acid is sulfuric acid, tetrafluoroboricacid, methanesulfonic acid, nitric acid, or hydrochloric acid. In someembodiments, the acid is sulfuric acid. In some embodiments, the acid ishydrochloric acid.

In some embodiments, the reaction conditions of step (e) comprise aco-solvent. In some embodiments, the co-solvent is an alcohol. In someembodiments, the co-solvent is 2-propanol, t-butanol, t-amyl alcohol,ethanol, or acetonitrile.

In some embodiments, the reaction conditions of step (e) comprise atemperature of about 5 and 10° C. In some embodiments, the reactionconditions of step (e) comprise a temperature between about 0 and about20° C. In some embodiments, the reaction conditions of step (e) comprisebetween about 2 and about 8° C.

5. Intermediate Compounds

Some embodiments provide herein intermediates useful for the synthesisof Compound 1 or methods of making such intermediates.

Some embodiments provide for a compound of formula, G-4-a:

Some embodiments provide for a compound of formula, G-4-b:

Some embodiments provide for a compound of formula, (R)-G-8:

wherein:

[acyl] is R^(x)C(O)—, wherein R^(x) is optionally substituted C₁₋₄aliphatic;

-   R^(a) is an optionally substituted group selected from a 3-7    membered ring having 0-2 heteroatoms selected from nitrogen, oxygen,    and sulfur, and a C₁₋₆ aliphatic;-   R² is hydrogen, or optionally substituted C₁₋₆ aliphatic; and

R⁵ is hydrogen or halogen.

In some embodiments, R^(x) is optionally substituted C₃₋₄ aliphatic.

Some embodiments provide for a compound of formula (R)-I-1:

wherein R^(x) is optionally substituted C₁₋₄ aliphatic.

Some embodiments provide for a compound of formula (R)-I-2:

wherein R^(x) is optionally substituted C₁₋₄ aliphatic.

Some embodiments provide for a compound of formula (R)-G-1:

wherein:

-   -   R^(H) is a leaving group;    -   R^(a) is an optionally substituted group selected from a 3-7        membered ring having 0-2 heteroatoms selected from nitrogen,        oxygen, and sulfur, and a C₁₋₆ aliphatic;    -   R² is hydrogen, or optionally substituted C₁₋₆ aliphatic; and    -   R⁵ is hydrogen or halogen.

Some embodiments provide for a compound of formula H-1:

wherein R^(H) is a leaving group.

Some embodiments provide for a compound of formula H-2:

wherein R^(H) is a leaving group.

In some embodiments, R^(H) is halogen or sulfonate. In some embodiments,R^(H) is bromo. In some embodiments, R^(H) is mesylate. In someembodiments, [acyl] is succinyl. In some embodiments, the [acyl] donoris succinic anhydride.

Some embodiments provide for a compound of formula:

or a salt thereof.

Some embodiments provide for a compound of formula:

or a salt thereof.6. Uses, Formulation and Administration and Pharmaceutically AcceptableCompositions

According to another embodiment, the invention provides a compositioncomprising a compound of this invention or a pharmaceutically acceptablesalt, ester, or salt of ester thereof and a pharmaceutically acceptablecarrier, adjuvant, or vehicle. Some embodiments provide for acomposition comprising a compound as described herein, or apharmaceutically acceptable salt or co-crystal thereof, and apharmaceutically acceptable carrier, adjuvant, or vehicle.

Some embodiments provide for a composition comprising a crystalline formof Compound 1 as described herein. The amount of compound incompositions of this invention is such that is effective to measurablyinhibit ACC, in a biological sample or in a patient. In certainembodiments, the amount of compound in compositions of this invention issuch that is effective to measurably inhibit ACC, in a biological sampleor in a patient. In certain embodiments, a composition of this inventionis formulated for administration to a patient in need of suchcomposition. In some embodiments, a composition of this invention isformulated for oral administration to a patient.

The term “compound” as used herein, means an ACC inhibitor of Formula I(including but not limited to Compound 1), or a solid form thereof. Insome embodiments, the term “compound” as used herein, means an ACCinhibitor of Formula I (including but not limited to Compound 1), or asalt or solid form thereof. In some embodiments, a compound is Compound1 or a pharmaceutically acceptable salt thereof. In some embodiments, acompound is the free acid of Compound 1. In some embodiments, a compoundis a solid form of Compound 1. In some embodiments, a compound is acrystalline form of Compound 1. In some embodiments, a compound is FormI, Form II, Form III, Form IV, Form V, Form VI, Form VII, or Form VIIIof Compound 1. In some embodiments, a compound is a polymorph of thefree acid of Compound 1. In some embodiments, a compound is Form I, FormVII, or Form VIII of Compound 1. In some embodiments, a compound is apseudopolymorph of the free acid of Compound 1. In some embodiments, acompound is Form I of Compound 1. In some embodiments, a compound isForm II of Compound 1. In some embodiments, a compound is Form III ofCompound 1. In some embodiments, a compound is Form IV of Compound 1. Insome embodiments, a compound is Form V of Compound 1. In someembodiments, a compound is Form VI of Compound 1. In some embodiments, acompound is Form VII of Compound 1. In some embodiments, a compound isForm VIII of Compound 1. In some embodiments, a compound is a solvate ofCompound 1. In some embodiments, a compound is amorphous Compound 1. Insome embodiments, a compound is a salt or co-crystal of Compound 1. Insome embodiments, a compound is Compound 1 Sodium Form I. In someembodiments, a compound is Compound 1 Sodium Form II. In someembodiments, a compound is Compound 1 Calcium Form I. In someembodiments, a compound is Compound 1 Magnesium Form I. In someembodiments, a compound is Compound 1 Diethanolamine Form I. In someembodiments, a compound is Compound 1 Piperazine Form I.

The term “patient,” as used herein, means an animal, preferably amammal, and most preferably a human.

The term “pharmaceutically acceptable carrier, adjuvant, or diluent”refers to a non-toxic carrier, adjuvant, or vehicle that does notdestroy the pharmacological activity of the compound with which it isformulated. Pharmaceutically acceptable carriers, adjuvants or diluentsthat may be used in the compositions of this invention include, but arenot limited to, antiadherents, binders, coatings, colorants,disintegrants, flavors, glidants, lubricants, preservatives, sorbents,and vehicles. Examples of carriers, adjuvants, and diluents include, butare not limited to, ion exchangers, alumina, aluminum stearate,lecithin, serum proteins, such as human serum albumin, buffer substancessuch as phosphates, glycine, sorbic acid, potassium sorbate, partialglyceride mixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

A “pharmaceutically acceptable derivative” means any non-toxic salt,ester, salt of an ester or other derivative of a compound of thisinvention that, upon administration to a recipient, is capable ofproviding, either directly or indirectly, a compound of this inventionor an inhibitorily active metabolite or residue thereof.

As used herein, the term “inhibitorily active metabolite or residuethereof” means that a metabolite or residue thereof is also an inhibitorof ACC. In some embodiments, the inhibitorily active metabolite orresidue thereof is selected from the following:

In some embodiments, the present invention provides a metabolite ofCompound 1, wherein the metabolite is the M+glucuronide conjugate. TheM+glucuronide conjugate has an IC₅₀ at ACC1 of 5 nM. In someembodiments, the present invention provides a metabolite of Compound 1,wherein the metabolite is a M-CH₃ demethylated metabolite. The M-CH₃metabolite of Compound 1 has an IC₅₀ at ACC1 of 22 nM. In someembodiments, a provided metabolite of Compound 1 is isolated.

Compositions of the present invention may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally or intravenously. Sterile injectable forms of thecompositions of this invention may be aqueous or oleaginous suspension.These suspensions may be formulated according to techniques known in theart using suitable dispersing or wetting agents and suspending agents.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium.

For this purpose, any bland fixed oil may be employed includingsynthetic mono- or di-glycerides. Fatty acids, such as oleic acid andits glyceride derivatives are useful in the preparation of injectables,as are natural pharmaceutically-acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions may also contain a long-chain alcohol diluentor dispersant, such as carboxymethyl cellulose or similar dispersingagents that are commonly used in the formulation of pharmaceuticallyacceptable dosage forms including emulsions and suspensions. Othercommonly used surfactants, such as Tweens, Spans and other emulsifyingagents or bioavailability enhancers which are commonly used in themanufacture of pharmaceutically acceptable solid, liquid, or otherdosage forms may also be used for the purposes of formulation.

Pharmaceutically acceptable compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers commonly used include lactose andcorn starch. Lubricating agents, such as magnesium stearate, are alsotypically added. For oral administration in a capsule form, usefuldiluents include lactose and dried cornstarch. When aqueous suspensionsare required for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

In some embodiments, a pharmaceutically acceptable compositioncomprising a form of Compound 1 as described herein is administered as acapsule. In some embodiments, a pharmaceutically acceptable compositioncomprising a form of Compound 1 as described herein is administered as atablet.

Alternatively, pharmaceutically acceptable compositions of thisinvention may be administered in the form of suppositories for rectaladministration. These can be prepared by mixing the agent with asuitable non-irritating excipient that is solid at room temperature butliquid at rectal temperature and therefore will melt in the rectum torelease the drug. Such materials include cocoa butter, beeswax andpolyethylene glycols.

Pharmaceutically acceptable compositions of this invention may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, provided pharmaceutically acceptablecompositions may be formulated in a suitable ointment containing theactive component suspended or dissolved in one or more carriers.Carriers for topical administration of compounds of this inventioninclude, but are not limited to, mineral oil, liquid petrolatum, whitepetrolatum, propylene glycol, polyoxyethylene, polyoxypropylenecompound, emulsifying wax and water. Alternatively, providedpharmaceutically acceptable compositions can be formulated in a suitablelotion or cream containing the active components suspended or dissolvedin one or more pharmaceutically acceptable carriers. Suitable carriersinclude, but are not limited to, mineral oil, sorbitan monostearate,polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol,benzyl alcohol and water.

For ophthalmic use, provided pharmaceutically acceptable compositionsmay be formulated as micronized suspensions in isotonic, pH adjustedsterile saline, or, preferably, as solutions in isotonic, pH adjustedsterile saline, either with or without a preservative such asbenzylalkonium chloride. Alternatively, for ophthalmic uses, thepharmaceutically acceptable compositions may be formulated in anointment such as petrolatum.

Pharmaceutically acceptable compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

Most preferably, pharmaceutically acceptable compositions of thisinvention are formulated for oral administration. Such formulations maybe administered with or without food. In some embodiments,pharmaceutically acceptable compositions of this invention areadministered without food. In other embodiments, pharmaceuticallyacceptable compositions of this invention are administered with food.

The amount of compounds of the present invention that may be combinedwith the carrier materials to produce a composition in a single dosageform will vary depending upon the host treated, the particular mode ofadministration. Preferably, provided compositions should be formulatedso that a dosage of between 0.01-100 mg/kg body weight/day of theinhibitor can be administered to a patient receiving these compositions.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of a compound of the present invention in the composition willalso depend upon the particular compound in the composition.

In some embodiments, a crystalline form of Compound 1 is administered ata dose of about 2 milligrams to about 500 milligrams per day, about 2milligrams to about 400 milligrams per day, about 2 milligrams to about300 milligrams per day, about 2 milligrams to about 200 milligrams perday, or about 2 milligrams to about 100 milligrams per day. In someembodiments, a crystalline form of Compound 1 is administered at a doseof about 5 milligrams per day, about 6 milligrams per day, about 7milligrams per day, about 8 milligrams per day, about 9 milligrams perday, about 10 milligrams per day, about 11 milligrams per day, about 12milligrams per day, about 13 milligrams per day, about 14 milligrams perday, about 15 milligrams per day, 16 milligrams per day, 17 milligramsper day, 18 milligrams per day, 19 milligrams per day, 20 milligrams perday, 21 milligrams per day, 22 milligrams per day, 23 milligrams perday, 24 milligrams per day, or 25 milligrams per day.

In some embodiments, a crystalline form of Compound 1 is administered ata dose of greater than about 5 milligrams per day, greater than about 10milligrams per day, greater than about 15 milligrams per day, greaterthan about 20 milligrams per day, greater than about 25 milligrams perday, greater than about 30 milligrams per day, greater than about 35milligrams per day, greater than about 40 milligrams per day, greaterthan about 45 milligrams per day, or greater than about 50 milligramsper day. In some embodiments, a crystalline form of Compound 1 isadministered at a dose of less than about 300 milligrams per day, lessthan about 275 milligrams per day, less than about 250 milligrams perday, less than about 225 milligrams per day, less than about 200milligrams per day, less than about 175 milligrams per day, less thanabout 150 milligrams per day, less than about 125 milligrams per day,less than about 100 milligrams per day.

In some embodiments, a crystalline form of Compound 1 is administered ata dose of about 5 milligrams once daily, about 20 milligrams once daily,about 30 milligrams once daily, about 50 milligrams once daily, about 80milligrams once daily, about 100 milligrams once daily, about 150milligrams once daily, about 200 milligrams once daily, about 500milligrams once daily, about 800 milligrams once daily, or about 1000milligrams once daily.

In some embodiments, a crystalline form of Compound 1 is administered ata dose of about 10 milligrams twice daily, about 25 milligrams twicedaily, about 50 milligrams twice daily, or about 100 milligrams twicedaily.

Pharmaceutical Uses

As used herein, the terms “treatment,” “treat,” and “treating” refer toreversing, alleviating, delaying the onset of, or inhibiting theprogress of a disease or disorder, or one or more symptoms thereof, asdescribed herein. In some embodiments, treatment may be administeredafter one or more symptoms have developed. In other embodiments,treatment may be administered in the absence of symptoms. For example,treatment may be administered to a susceptible individual prior to theonset of symptoms (e.g., in light of a history of symptoms and/or inlight of genetic or other susceptibility factors). Treatment may also becontinued after symptoms have resolved, for example to prevent or delaytheir recurrence.

The term “therapeutically effective amount” refers to an amount of thecompound as described herein that is sufficient to effect treatment asdefined above, when administered to a patient (particularly a human) inneed of such treatment in one or more doses. The therapeuticallyeffective amount will vary, depending upon the patient, the diseasebeing treated, the weight and/or age of the patient, the severity of thedisease, or the manner of administration as determined by a qualifiedprescriber or care giver.

Acetyl-CoA carboxylase (ACC) catalyzes the ATP-dependent carboxylationof acetyl-CoA to form malonyl-CoA. This reaction, which proceeds in twohalf-reactions, a biotin carboxylase (BC) reaction and acarboxyltransferase (CT) reaction, is the first committed step in fattyacid (FA) biosynthesis and is the rate-limiting reaction for thepathway. In addition to its role as a substrate in FA biosynthesis,malonyl-CoA, the product of the ACC-catalyzed reaction, also plays animportant regulatory role in controlling mitochondrial FA uptake throughallosteric inhibition of carnitine palmitoyltransferase I (CPT-I), theenzyme catalyzing the first committed step in mitochondrial FAoxidation. Malonyl-CoA, therefore, is a key metabolic signal for thecontrol of FA production and utilization in response to dietary changesand altered nutritional requirements in animals, for example duringexercise, and therefore plays a key role in controlling the switchbetween carbohydrate and fat utilization in liver and skeletal muscle(Harwood, 2005).

In mammals, ACC exists as two tissue-specific isozymes, ACC1 which ispresent in lipogenic tissues (liver, adipose) and ACC2, which is presentin oxidative tissues (liver, heart, skeletal muscle). ACC1 and ACC2 areencoded by separate genes, display distinct cellular distributions, andshare 75% overall amino acid sequence identity, except for an extensionat the N-terminus of ACC2 that direct ACC2 to the mitochondrialmembrane. ACC1, which lacks this targeting sequence, is localized to thecytoplasm. In the heart and skeletal muscle, which have a limitedcapacity to synthesize fatty acids, the malonyl-CoA formed by ACC2functions to regulate FA oxidation. In the liver, the malonyl-CoA formedin the cytoplasm through the actions of ACC1 is utilized for FAsynthesis and elongation leading to triglyceride formation and VLDLproduction, whereas the malonyl-CoA formed at the mitochondrial surfaceby ACC2 acts to regulate FA oxidation (Tong and Harwood, J. CellularBiochem. 99: 1476, 2006). This compartmentalization of malonyl-CoAresults from a combination of synthesis proximity (Abu-Elheiga et al.,PNAS (USA) 102: 12011, 2005) and the rapid action of malonyl-CoAdecarboxylase (Cheng et al., J. Med. Chem. 49:1517, 2006).

Simultaneous inhibition of the enzymatic activities of ACC1 and ACC2offers the ability to inhibit de novo FA production in lipogenic tissues(e.g. liver & adipose) while at the same time stimulating FA oxidationin oxidative tissues (e.g. liver & skeletal muscle) and therefore offersan attractive modality for favorably affecting, in a concerted manner, amultitude of cardiovascular risk factors associated with obesity,diabetes, insulin resistance, and the metabolic syndrome.

Several lines of evidence strongly support the concept of directinhibition of ACC activity as an important therapeutic target fortreating obesity, diabetes, insulin resistance, and the metabolicsyndrome.

Abu-Elheiga et al. (Proc. Natl. Acad. Sci. USA 100:10207-10212, 2003)demonstrated that ACC2 knock-out mice exhibit reduced skeletal andcardiac muscle malonyl-CoA, increased muscle FA oxidation, reducedhepatic fat, reduced total body fat, elevated skeletal muscle uncouplingprotein-3 (UCP3) which is indicative of increased energy expenditure,reduced body weight, reduced plasma free FAs, reduced plasma glucose,and reduced tissue glycogen, and are protected from diet-induceddiabetes and obesity.

Savage et al. (J. Clin. Invest. 116: 817, 2006), using ACC1 and ACC2antisense oligonucleotides, demonstrated stimulation of FA oxidation inisolated rat hepatocytes and in rats fed high-fat diets, and lowering ofhepatic triglycerides, improvements in insulin sensitivity, reductionsin hepatic glucose production, and increases in UCP1 mRNA in highfat-fed rats. These effects were greater when both ACC1 and ACC2expression were suppressed than when either ACC1 or ACC2 expressionalone was suppressed.

Harwood et al. (J. Biol. Chem. 278: 37099, 2003) demonstrated that theisozyme-nonselective ACC inhibitor, CP-640186, which equally inhibitsACC1 and ACC2 (IC₅₀=˜60 nM) isolated from rat, mouse, monkey and humanwithout inhibiting either pyruvate carboxylase or propionyl-CoAcarboxylase, reduced FA synthesis, triglyceride synthesis and secretionin Hep-G2 cells without affecting cholesterol synthesis, and reducedapoB secretion without affecting apoA1 secretion. CP-640186 alsostimulated FA oxidation in C2C12 cells and in rat muscle slices andincreased CPT-I activity in Hep-G2 cells. In experimental animals,CP-640186 acutely reduced malonyl-CoA concentration in both lipogenicand oxidative tissues in both the fed and fasted state, reduced liverand adipose tissue FA synthesis, and increased whole body FA oxidation.In sucrose-fed rats treated with CP-640186 for three weeks, CP-640186time- and dose-dependently reduced liver, muscle and adiposetriglycerides, reduced body weight due to selective fat reductionwithout reducing lean body mass, reduced leptin levels, reduced thehyperinsulinemia produced by the high sucrose diet without changingplasma glucose levels, and improved insulin sensitivity.

Saha et al. (Diabetes 55:A288, 2006) demonstrated stimulation of insulinsensitivity in insulin-resistant rat muscle tissue by CP-640186 within30 min of compound administration, and studies by Furler et al.(Diabetes 55:A333, 2006) used dual tracer analysis to show that acute(46 min) treatment of rats with CP-640186 stimulated FA clearancewithout decreasing glucose clearance.

ACC is the rate-limiting enzyme in fatty acid synthesis and its product,malonyl CoA, serves as an important regulator of fatty acid oxidation.Hence, ACC inhibitors both reduce de novo lipid synthesis and promotethe oxidation of existing fat. This dual effect on lipid metabolismraises the possibility that ACC inhibitors will be substantially moreeffective in reducing excess fat than other mechanisms. Furthermore, ACCinhibitors will impact insulin sensitivity, plasma and tissuetriglycerides, and fasting plasma glucose as a consequence of whole-bodyand tissue-specific fat mass reduction without the need forpoly-pharmacy.

For the treatment of obesity and other metabolic disorders, ACCinhibitors need only access the liver and muscle in the peripheralcompartment. For oncological indications, tumor penetration is alsorequired. However, avoiding the CNS will address many of side effectsassociated with the late-stage obesity programs targeting CNS receptors.ACC inhibitors are also expected to have superior safety profiles toexisting metabolic disease agents. For example, it is unlikely that anACC inhibitor will precipitate life-threatening hypoglycemia as is oftenseen with insulin mimetics, insulin secretagogues, and insulindegradation inhibitors. Also, since ACC inhibitors will reducewhole-body fat mass, they will be superior to the glitazones thatincrease whole-body fat mass as part of their mechanism of action.

A peripherally acting agent that causes significant weight loss andimproves other metabolic endpoints fits well within the U.S. FDA'srequirements for approval of a new obesity agent. However, if anapproval for obesity continues to be challenging in 5-7 years, ACCinhibitors could be approved for familial combined hyperlipidemia andnon-alcoholic steatohepatitis (NASH). There are currently no marketedACC inhibitors, so an isozyme-nonselective ACC inhibitor would representfirst-in-class therapy for treating obesity and metabolic syndrome, inaddition to other disorders mediated by ACC enzymes.

The activity of a provided compound as an inhibitor of ACC or treatmentfor obesity or metabolic syndrome, may be assayed in vitro or in vivo.An in vivo assessment of the efficacy of the compounds of the inventionmay be made using an animal model of obesity or metabolic syndrome,e.g., a rodent or primate model. Cell-based assays may be performedusing, e.g., a cell line isolated from a tissue that expresses ACC.Additionally, biochemical or mechanism-based assays, e.g., transcriptionassays using a purified protein, Northern blot, RT-PCR, etc., may beperformed. In vitro assays include assays that determine cellmorphology, protein expression, and/or the cytotoxicity, enzymeinhibitory activity, and/or the subsequent functional consequences oftreatment of cells with compounds of the invention. Alternate in vitroassays quantitate the ability of the inhibitor to bind to protein ornucleic acid molecules within the cell. Inhibitor binding may bemeasured by radiolabeling the inhibitor prior to binding, isolating theinhibitor/target molecule complex and determining the amount ofradiolabel bound. Alternatively, inhibitor binding may be determined byrunning a competition experiment where new inhibitors are incubated withpurified proteins or nucleic acids bound to known radioligands. Detailedconditions for assaying a compound utilized in this invention as aninhibitor of ACC are set forth in the Examples below. The aforementionedassays are exemplary and not intended to limit the scope of theinvention. The skilled practitioner can appreciate that modificationscan be made to conventional assays to develop equivalent assays thatobtain the same result.

A provided compound or composition thereof may be administered using anyamount and any route of administration effective for treating orlessening the severity of a metabolic disorder or condition, cancer, abacterial infection, a fungal infection, a parasitic infection (e.g.malaria), an autoimmune disorder, a neurodegenerative or neurologicaldisorder, schizophrenia, a bone-related disorder, liver disease, or acardiac disorder.

In some embodiments, a provided compound or composition thereof may beadministered using any amount and any route of administration effectivefor treating or lessening the severity of a disease associated with ACC(Tong et al. “Acetyl-coenzyme A carboxylase: crucial metabolic enzymeand attractive target for drug discovery” Cell and Molecular LifeSciences (2005) 62, 1784-1803).

In some embodiments, a provided compound or composition thereof may beadministered using any amount and any route of administration effectivefor treating or lessening the severity of a metabolic disorder, disease,or condition. In some embodiments, the metabolic disorder is obesity,metabolic syndrome, diabetes or diabetes-related disorders includingType 1 diabetes (insulin-dependent diabetes mellitus, IDDM) and Type 2diabetes (non-insulin-dependent diabetes mellitus, NIDDM), impairedglucose tolerance, insulin resistance, hyperglycemia, diabeticcomplications, including, but not limited to atherosclerosis, coronaryheart disease, stroke, peripheral vascular disease, nephropathy,hypertension, neuropathy and nephropathy; obesity comorbiditiesincluding but not limited to metabolic syndrome, dyslipidemia,hypertension, insulin resistance, diabetes (including Type 1 and Type 2diabetes), coronary artery disease, and heart failure. In someembodiments, the metabolic disorder, disease or condition isnon-alcoholic fatty liver disease or hepatic insulin resistance. In someembodiments, the metabolic disorder is non-alcoholic steatohepatitis.

Combination Therapy

In some embodiments, the present invention provides a method of treatinga metabolic disorder, disease, or condition described herein, comprisingadministering a compound of the invention in conjunction with one ormore pharmaceutical agents. Suitable pharmaceutical agents that may beused in combination with the compounds of the present invention includeanti-obesity agents (including appetite suppressants), anti-diabeticagents, anti-hyperglycemic agents, lipid lowering agents, andanti-hypertensive agents.

Suitable lipid lowering agents that can be used in conjunction with aprovided compound or composition thereof include but are not limited to,bile acid sequestrants, HMG-CoA reductase inhibitors, HMG-CoA synthaseinhibitors, cholesterol absorption inhibitors, acyl coenzymeA-cholesterol acyl transferase (ACAT) inhibitors, CETP inhibitors,squalene synthetase inhibitors, PPAR-alpha agonists, FXR receptormodulators, LXR receptor modulators, lipoprotein synthesis inhibitors,renin-angiotensin system inhibitors, PPAR-delta partial agonists, bileacid reabsorption inhibitors, PPAR-gamma agonists, triglyceridesynthesis inhibitors, microsomal triglyceride transport inhibitors,transcription modulators, squalene epoxidase inhibitors, low densitylipoprotein receptor inducers, platelet aggregation inhibitors, 5-LO orFLAP inhibitors, niacin, and niacin-bound chromium.

Suitable anti-hypertensive agents that can be used in conjunction with aprovided compound or composition thereof include but are not limited todiuretics, beta-adrenergic blockers, calcium channel blockers,angiotensin converting enzyme (ACE) inhibitors, neutral endopeptidaseinhibitors, endothelin antagonists, vasodilators, angiotensin IIreceptor antagonists, alpha/beta adrenergic blockers, alpha 1 blockers,alpha 2 agonists, aldosterone inhibitors, mineralocorticoid receptorinhibitors, renin inhibitors, and angiopoietin 2 binding agents.

Suitable anti-diabetic agents that can be used in conjunction with aprovided compound or composition thereof include but are not limited toother acetyl-CoA carboxylase (ACC) inhibitors, DGAT-1 inhibitors,AZD7687, LCQ908, DGAT-2 inhibitors, monoacylglycerol O-acyltransferaseinhibitors, PDE-10 inhibitors, AMPK activators, sulfonylureas (e.g.acetohexamide, chlorpropamide, diabinese, glibenclamide, glipizide,glyburide, blimipiride, gliclazide, glipentide, gliquidone, glisolamide,tolazamide, tolbutamide), meglitinides, alpha-amylase inhibitors (e.g.tendamistat, treastatin, AL-3688), alpha-glucoside hydrolase inhibitors(e.g. acarbose), alpha-glucosidase inhibitors (e.g. adiposine,camiglibose, emiglitate, miglitol, voglibose, pradimicin-Q,sarbostatin), PPAR-gamma agonists (e.g. balaglitazone, ciglitazone,darglitazone, englitazone, isaglitazone, pioglitazone, rosiglitazone,troglitazone), PPAR-alpha/gamma agonists (e.g. CLX-0940, GW-1536,GW-1929, GW-2433, KRP-297, L-796449, LR-90, MK-0767, SB-219994),biguanides (e.g. metformin, buformin), GLP-1 modulators (exendin-3,exendin-4), liraglutide, albiglutide, exenatide (Byetta), taspoglutide,lixisenatide, dulaglutide, semaglutide, N,N-9924, TTP-054, PTP-1Binhibitors (trodusquemine, hyrtiosal extract), SIRT-1 inhibitors (e.g.resveratrol, GSK2245840, GSK184072), DPP-IV inhibitors (e.g.sitagliptin, vildagliptin, alogliptin, dutogliptin, linagliptin,saxagliptin), insulin secretagogues, fatty acid oxidation inhibitors, A2antagonists, JNK inhibitors, glucokinase activators (e.g. TTP-399,TTP-355, TTP-547, AZD1656, ARRY403, MK-0599, TAK-329, AZD5658, GKM-001),insulin, insulin mimetics, glycogen phosphorylase inhibitors (e.g.GSK1362885), VPAC2 receptor agonists, SGLT2 inhibitors (dapagliflozin,canagliflozin, BI-10733, tofogliflozin, ASP-1941, THR1474, TS-071,ISIS388626, LX4211), glucagon receptor modulators, GPR119 modulators(e.g. MBX-2982, GSK1292263, APD597, PSN821), FGF21 derivatives, TGR5(GPBAR1) receptor agonists (e.g. INT777), GPR40 agonists (e.g. TAK-875),GPR120 agonists, nicotinic acid receptor (HM74A) activators, SGLT1inhibitors (e.g. GSK1614235), carnitine palmitoyl transferase enzymeinhibitors, fructose 1,6-diphosphatase inhibitors, aldose reductaseinhibitors, mineralocorticoid receptor inhibitors, TORC2 inhibitors,CCR2 inhibitors, CCR5 inhibitors, PKC (e.g. PKC-alpha, PKC-beta,PKC-gamma) inhibitors, fatty acid synthetase inhibitors, serinepalmitoyl transferase inhibitors, GPR81 modulators, GPR39 modulators,GPR43 modulators, GPR41 modulators, GPR105 modulators, Kv1.3 inhibitors,retinol binding protein 4 inhibitors, glucocorticoid receptormodulators, somatostatin receptor (e.g. SSTR1, SSTR2, SSTR3, SSTR5)inhibitors, PDHK2 inhibitors, PDHK4 inhibitors, MAP4K4 inhibitors,IL1-beta modulators, and RXR-alpha modulators.

Suitable anti-obesity agents include but are not limited to,11-beta-hydroxysteroid dehydrogenase 1 inhibitors, stearoyl-CoAdesaturase (SCD-1) inhibitors, MCR-4 agonists, CCK-A agonists, monoaminereuptake inhibitors (e.g. sibutramine), sympathomimetic agents,beta-3-adrenergic receptor agonists, dopamine receptor agonists (e.g.bromocriptine), melanocyte-stimulating hormone and analogs thereof,5-HT2C agonists (e.g. lorcaserin/Belviq), melanin concentrating hormoneantagonists, leptin, leptin analogs, leptin agonists, galaninantagonists, lipase inhibitors (e.g. tetrahydrolipstatin/Orlistat),anorectic agents (e.g. bombesin agonists), NPY antagonists (e.g.velneperit), PYY₃₋₃₆ (and analogs thereof), BRS3 modulators, opioidreceptor mixed antagonists, thyromimetic agents, dehydroepiandrosterone,glucocorticoid agonists or antagonists, orexin antagonists, GLP-1agonists, ciliary neurotrophic factors (e.g. Axokine), humanagouti-related protein (AGRP) inhibitors, H3 antagonists or inverseagonists, neuromedin U agonists, MTP/ApoB inhibitors (e.g. gut-selectiveMTP inhibitors such as dirlotapide, JTT130, Usistapide, SLX4090), MetAp2inhibitors (e.g. ZGN-433), agents with mixed modulatory activity at twoor more of glucagon, GIP, and GLP1 receptors (e.g. MAR-701, ZP2929),norepinephrine reuptake inhibitors, opioid antagonists (e.g.naltrexone), CB1 receptor antagonists or inverse agonists, ghrelinagonists or antagonists, oxyntomodulin and analogs thereof, monoamineuptake inhibitors (e.g. tesofensine), and combination agents (e.g.buproprion plus zonisamide (Empatic), pramlintide plus metreleptin,buproprion plus naltrexone (Contrave), phentermine plus topiramate(Qsymia).

In some embodiments, the anti-obesity agents used in combination with aprovided compound or composition thereof are selected from gut-selectiveMTP inhibitors (e.g. dirlotapide, mitratapide, implitapide, R56918),CCK-A agonists, 5-HT2C agonists (e.g. lorcaserin/Belviq), MCR4 agonists,lipase inhibitors (e.g. Cetilistat), PYY₃₋₃₆ (including analogs andPEGylated analogs thereof), opioid antagonists (e.g. naltrexone), oleoylestrone, obinepitide, pramlintide, tesofensine, leptin, bromocriptine,orlistat, AOD-9604, and sibutramine.

In some embodiments, a provided compound or composition, according tothe method of the present invention, may be administered using anyamount and any route of administration effective for treating orlessening the severity of a LKB1 or Kras associated disease. In someembodiments, the LKB1 or Kras associated disease is selected fromhepatocellular carcinoma, LKB1 mutant cancers, LKB1 loss ofheterozygosity (LOH) driven cancers, Kras mutant cancers, Peutz-Jegherssyndrome (PJS), Cowden's disease (CD), and tubeous sclerosis (TS)(Makowski et al. “Role of LKB1 in Lung Cancer Development” BritishJournal of Cancer (2008) 99, 683-688). In some embodiments, the LKB1 orKras associated disease is a Kras positive/LKB1 deficient lung tumor.

In some embodiments, a provided compound or composition, according tothe method of the present invention, may be administered using anyamount and any route of administration effective for treating orlessening the severity of a cancer, or inhibiting the growth of orinducing apoptosis in cancer cells (Wang et al. “Acetyl-CoACarboxylase-alpha Inhibitor TOFA Induces Human Cancer Cell Apoptosis”Biochem Biophys Res Commun. (2009) 385(3), 302-306; Chajes et al.“Acetyl-CoA Carboxylase alpha Is Essential to Breast Cancer CellSurvival” Cancer Res. (2006) 66, 5287-5294; Beckers et al. “ChemicalInhibition of Acetyl-CoA Carboxylase Induces Growth Arrest andCytotoxicity Selectivity in Cancer Cells” Cancer Res. (2007) 8180-8187;Brusselmans et al. “RNA Interference-Mediated Silencing of theAcetyl-CoA-Carboxylase-alpha Gene Induces Growth Inhibition andApoptosis of Prostate Cancer Cells” Cancer Res. (2005) 65, 6719-6725;Brunet et a. “BRCA1 and Acetyl-CoA Carboxylase: The Metabolic Syndromeof Breast Cancer” Molecular Carcinogenesis (2008) 47, 157-163; Cairns etal. “Regulation of Cancer Cell Metabolism” (2011) 11, 85-95; Chiaradonnaet al. “From Cancer Metabolism to New Biomarkers and Drug Targets”Biotechnology Advances (2012) 30, 30-51).

In some embodiments, a provided compound or composition, according tothe method of the present invention, may be administered using anyamount and any route of administration effective for treating orlessening the severity of a melanoma. In some embodiments, the melanomais one bearing an activated MAPK pathway (Petti et al. “AMPK activatorsinhibit the proliferation of human melanomas bearing the activated MAPKpathway” Melanoma Research (2012) 22, 341-350).

A provided compound finds special utility in triple negative breastcancer, as the tumor suppressor protein BRCA1 binds and stabilizes theinactive form of ACC, thus regulating de novo lipid synthesis. Deletionor mutation of this tumor suppressor protein results in the loss of thebinding and stabilization of the inactive form of ACC, resulting inincreased capacity for ACC-driven de novo lipogenesis, resulting incancer cell proliferation. See Brunet et al. “BRCA1 and acetyl-CoAcarboxylase: the metabolic syndrome of breast cancer” Mol. Carcinog.(2008) 47(2), 157-163.

In some embodiments, a provided compound or composition, according tothe method of the present invention, may be administered using anyamount and any route of administration effective for treating orlessening the severity of a liposarcoma. Liposarcomas have been shown todepend on de novo long-chain fatty acid synthesis for growth, andinhibition of ACC by soraphen A inhibited lipogenesis as well as tumorcell growth (Olsen et at. “Fatty acid synthesis is a therapeutic targetin human liposarcoma” International J. of Oncology (2010) 36,1309-1314).

In some embodiments, a provided compound or composition, according tothe method of the present invention, may be administered using anyamount and any route of administration effective for treating orlessening the severity of a liver disease. In some embodiments, theliver disease is selected from alcoholic fatty liver disease (AFLD),familial combined hyperlipidemia, hepatitis (including hepatitis A,hepatitis B, and hepatitis C), hepatocellular carcinoma, non-alcoholicfatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), livercancer, liver fibrosis, liver inflammation, cholangiocarcinoma,angiosarcoma, hemangiosarcoma, and progressive familial intrahepaticcholestasis. In some embodiments, the liver disease is non-alcoholicsteatoheptatitis. In some embodiments, the liver disease ishepatocellular carcinoma.

Some embodiments provided herein provide for methods of treatingnon-alcoholic steatohepatitis (NASH) comprising administering atherapeutically effective amount of a crystalline form of Compound 1 asdescribed herein or a composition as described herein.

Some embodiments provided herein provide for the use of a crystallineform of Compound 1 as described herein or a composition as describedherein in the treatment of treating non-alcoholic steatohepatitis(NASH).

Some embodiments provided herein provide for methods of treatingnon-alcoholic steatohepatitis (NASH) comprising administering atherapeutically effective amount of Form I of Compound 1 or acomposition comprising Form I of Compound 1.

Some embodiments provided herein provide for the use of Form I ofCompound 1 or a composition comprising Form I of Compound 1 in thetreatment of treating non-alcoholic steatohepatitis (NASH).

Some embodiments provided herein provide for methods of treatinghepatocellular carcinoma (HCC) comprising administering atherapeutically effective amount of a crystalline form of Compound 1 asdescribed herein or a composition as described herein. Some embodimentsprovided herein provide for the use of a crystalline form of Compound 1as described herein or a composition as described herein in thetreatment of HCC. In some embodiments, a crystalline form of Compound 1is administered as an adjuvant therapy. In some embodiments, thecrystalline form of Compound 1 or composition described herein areadministered after curative surgery, local ablation, or livertransplantation.

Some embodiments provided herein provide for methods of treatinghepatocellular carcinoma (HCC) comprising administering atherapeutically effective amount of Form I of Compound 1 or acomposition comprising Form I of Compound 1.

In some embodiments, a method of treating hepatocellular carcinoma (HCC)comprises administering a therapeutically effective amount of acrystalline form of Compound 1 as described herein or a composition asdescribed herein in combination with surgical resection, livertransplantation, radiofrequency ablation, percutaneous ethanolinjection, transarterial embolization, radiation, or chemotherapy. Insome embodiments, a method of treating hepatocellular carcinoma (HCC)comprises administering a therapeutically effective amount of Form I ofCompound 1 or a composition comprising Form I of Compound 1 incombination with surgical resection, liver transplation, radiofrequencyablation, percutaneous ethanol injection, transarterial embolization,radiation, or chemotherapy.

In some embodiments, a provided compound or composition, according themethod of the present invention, may be administered in combination withsorafenib for the treatment of hepatocellular carcinoma.

In some embodiments, a provided compound or composition, according tothe method of the present invention, may be administered using anyamount and any route of administration effective for treating orlessening the severity of a bacterial infection or inhibiting the growthof bacteria. In some embodiments, the bacterial infection is acnevulgaris.

In some embodiments, a provided compound or composition, according tothe method of the present invention, may be administered using anyamount and any route of administration effective for treating orlessening the severity of a fungal infection or inhibiting the growth offungal cells (Shen et al. “A Mechanism for the Potent Inhibition ofEukaryotic Acetyl-Coenzyme A Carboxylase by Soraphen A, a MacrocyclicPolyketide Natural Product” Molecular Cell (2004) 16, 881-891).

In some embodiments, a provided compound inhibits one or more species offungi at an MIC of 2 μg/mL or less. In some embodiments, a compound ofthe present invention inhibits at least one of C. albicans, C. krusei,and C. parapsilosis at a concentration of 2 μg/mL or less. In someembodiments, a compound of the present invention inhibits at least oneof C. albicans, C. krusei, and C. parapsilosis at a concentration of 1μg/mL or less. In some embodiments, a compound of the present inventioninhibits at least two of C. albicans, C. krusei, and C. parapsilosis ata concentration of 2 μg/mL or less. In some embodiments, a compound ofthe present invention inhibits at least two of C. albicans, C. krusei,and C. parapsilosis at a concentration of 1 μg/mL or less. In someembodiments, a compound of the present invention inhibits each of C.albicans, C. krusei, and C. parapsilosis at a concentration of 2 μg/mLor less. In some embodiments, a compound of the present inventioninhibits each of C. albicans, C. krusei, and C. parapsilosis at aconcentration of 1 μg/mL

In some embodiments, a provided compound inhibits at least one ofBotrtyis cinerea, Collectotrichum graminicola, Diplodia maydis, Fusariummoniliforme, Fusarium virguliforme, Phytophthora capsici, Rhizoctoniasolani, and Septoria at a concentration of 2 μg/mL or less. In someembodiments, a provided compound inhibits at least one of Botrtyiscinerea, Collectotrichum graminicola, Diplodia maydis, Fusariummoniliforme, Fusarium virguliforme, Phytophthora capsici, Rhizoctoniasolani, and Septoria at a concentration of 1 μg/mL or less. In someembodiments, a compound of the present invention inhibits at least twoof Botrtyis cinerea, Collectotrichum graminicola, Diplodia maydis,Fusarium moniliforme, Fusarium virguliforme, Phytophthora capsici,Rhizoctonia solani, and Septoria at a concentration of 2 μg/mL or less.In some embodiments, a compound of the present invention inhibits atleast two of Botrtyis cinerea, Collectotrichum graminicola, Diplodiamaydis, Fusarium moniliforme, Fusarium virguliforme, Phytophthoracapsici, Rhizoctonia solani, and Septoria at a concentration of 1 μg/mLor less. In some embodiments, a compound of the present inventioninhibits at least three of Botrtyis cinerea, Collectotrichumgraminicola, Diplodia maydis, Fusarium moniliforme, Fusariumvirguliforme, Phytophthora capsici, Rhizoctonia solani, and Septoria ata concentration of 2 g/mL or less. In some embodiments, a compound ofthe present invention inhibits at least three of Botrtyis cinerea,Collectotrichum graminicola, Diplodia maydis, Fusarium moniliforme,Fusarium virguliforme, Phytophthora capsici, Rhizoctonia solani, andSeptoria at a concentration of 1 μg/mL or less.

In some embodiments, a provided compound or composition, according tothe method of the present invention, may be administered using anyamount and any route of administration effective for treating orlessening the severity of a bacterial infection (Tong, L. et al. J.Cell. Biochem. (2006) 99, 1476-1488).

In some embodiments, a provided compound or composition, according tothe method of the present invention, may be administered using anyamount and any route of administration effective for treating orlessening the severity of a viral infection (Munger et al. Nat.Biotechnol. (2008) 26, 1179-1186). In some embodiments, the viralinfection is Hepatitis C. In some embodiments, the viral infection isHepatitis B. In some embodiments, the viral infection is Hepatitis A.

In some embodiments, a provided compound or composition, according tothe method of the present invention, may be administered using anyamount and any route of administration effective for treating orlessening the severity of a neurological disease (Henderson et al.Neurotherapeutics (2008) 5, 470-480; Costantini et al. Neurosci. (2008)9 Suppl. 2:S16; Baranano et al. Curr. Treat. Opin. Neurol. (2008) 10,410-419).

In some embodiments, a provided compound or composition, according tothe method of the present invention, may be administered using anyamount and any route of administration effective for treating orlessening the severity of a parasitic infection or inhibiting the growthof parasites (e.g. malaria and toxoplasma: Gornicki et al. “Apicoplastfatty acid biosynthesis as a target for medical intervention inapicomplexan parasites” International Journal of Parasitology (2003) 33,885-896; Zuther et al. “Growth of Toxoplasma gondii is inhibited byaryloxyphenoxypropionate herbicides targeting acetyl-CoA carboxylase”PNAS (1999) 96 (23) 13387-13392).

In some embodiments, a provided compound or composition, according tothe method of the present invention, may be administered using anyamount and any route of administration effective for treating orlessening the severity of a cardiac disorder. In some embodiments, thecardiac disorder is cardiac hypertrophy. In some embodiments the cardiacdisorder is treated or its severity lessened by the cardioprotectivemechanism resulting from increased fatty acid oxidation via ACCinhibition (Kolwicz et al. “Cardiac-specific deletion of acetyl CoAcarboxylase 2 (ACC2) prevents metabolic remodeling duringpressure-overload hypertrophy” Circ. Res. (2012); DOI:10.1161/CIRCRESAHA.112.268128).

In certain embodiments, a provided compound or composition, according tothe method of the present invention, may be used as herbicides. In someembodiments, the present invention provides a method to inhibit thegrowth or viability of plants comprising treating plants with compoundsof the present invention. In some embodiments of the present invention,a provided compound or composition can be used to inhibit the growth orviability of plants by inhibiting ACC. In some embodiments, the methodof the present invention comprises using a provided compound orcomposition to inhibit fatty acid production in or increase fatty acidoxidation in plants.

The exact amount required will vary from subject to subject, dependingon the species, age, and general condition of the subject, the severityof the infection, the particular agent, its mode of administration, andthe like. A provided compound or composition of the invention ispreferably formulated in dosage unit form for ease of administration anduniformity of dosage. The expression “dosage unit form” as used hereinrefers to a physically discrete unit of agent appropriate for thepatient to be treated. It will be understood, however, that the totaldaily usage of a provided compound or composition of the presentinvention will be decided by the attending physician within the scope ofsound medical judgment. The specific effective dose level for anyparticular patient or organism will depend upon a variety of factorsincluding the disorder being treated and the severity of the disorder;the activity of the specific compound employed; the specific compositionemployed; the age, body weight, general health, sex and diet of thepatient; the time of administration, route of administration, and rateof excretion of the specific compound employed; the duration of thetreatment; drugs used in combination or coincidental with the specificcompound employed, and like factors well known in the medical arts.

A pharmaceutically acceptable composition of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, a provided compound of the invention may beadministered orally or parenterally at dosage levels of about 0.01 mg/kgto about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg,of subject body weight per day, one or more times a day, to obtain thedesired therapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a provided compound, it is oftendesirable to slow the absorption of a compound from subcutaneous orintramuscular injection. This may be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the compound then depends upon itsrate of dissolution that, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered compound form is accomplished by dissolving or suspending acompound in an oil vehicle. Injectable depot forms are made by formingmicroencapsule matrices of a compound in biodegradable polymers such aspolylactide-polyglycolide. Depending upon the ratio of compound topolymer and the nature of the particular polymer employed, the rate ofcompound release can be controlled. Examples of other biodegradablepolymers include poly(orthoesters) and poly(anhydrides). Depotinjectable formulations are also prepared by entrapping a compound inliposomes or microemulsions that are compatible with body tissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polyethylene glycols and the like.

A provided compound can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, and eye drops are also contemplatedas being within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

According to one embodiment, the invention relates to a method ofinhibiting ACC in a biological sample comprising the step of contactingsaid biological sample with a provided compound, or a compositioncomprising said compound.

In certain embodiments, the invention relates to a method of modulatingfatty acid levels in a biological sample comprising the step ofcontacting said biological sample with a provided compound, or acomposition comprising said compound.

The term “biological sample”, as used herein, includes, withoutlimitation, cell cultures or extracts thereof; biopsied materialobtained from a mammal or extracts thereof; and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.

Inhibition of enzymes in a biological sample is useful for a variety ofpurposes that are known to one of skill in the art. Examples of suchpurposes include, but are not limited to biological assays, geneexpression studies, and biological target identification.

Another embodiment of the present invention relates to a method ofinhibiting ACC in a patient comprising the step of administering to saidpatient a provided compound, or a composition comprising said compound.

According to another embodiment, the invention relates to a method ofinhibiting fatty acid production, stimulating fatty acid oxidation, orboth, in a patient comprising the step of administering to said patienta provided compound, or a composition comprising said compound.According to certain embodiments, the invention relates to a method ofinhibiting fatty acid production, stimulating fatty acid oxidation, orboth in a patient, leading to decreasing obesity or alleviating symptomsof metabolic syndrome, comprising the step of administering to saidpatient a provided compound, or a composition comprising said compound.In other embodiments, the present invention provides a method fortreating a disorder mediated by ACC, in a patient in need thereof,comprising the step of administering to said patient a provided compoundor pharmaceutically acceptable composition thereof. Such disorders aredescribed in detail herein.

In some embodiments, a provided compound or composition thereof may beused in a method of treating obesity or another metabolic disorder. Incertain embodiments, a provided compound or composition thereof may beused to treat obesity or other metabolic disorder in a mammal. Incertain, embodiments the mammal is a human patient. In certainembodiments, a provided compound or composition thereof may be used totreat obesity or other metabolic disorder in a human patient.

In some embodiments, the present invention provides a method of treatingobesity or another metabolic disorder, comprising administering aprovided compound or composition thereof to a patient with obesity oranother metabolic disorder. In certain embodiments, the method oftreating obesity or another metabolic disorder comprises administering aprovided compound or composition thereof to a mammal. In certainembodiments, the mammal is a human. In some embodiments, the metabolicdisorder is dyslipidemia or hyperlipidemia. In some embodiments, theobesity is a symptom of Prader-Willi syndrome, Bardet-Biedl syndrome,Cohen syndrome or MOMO syndrome. In some embodiments, the obesity is aside effect of the administration of another medication, including butnot limited to insulin, sulfonylureas, thiazolidinediones,antipsychotics, antidepressants, steroids, anticonvulsants (includingphenytoin and valproate), pizotifen, or hormonal contraceptives.

In certain embodiments, the present invention provides a method oftreating cancer or another proliferative disorder, comprisingadministering a provided compound or composition thereof to a patientwith cancer or another proliferative disorder. In certain embodiments,the method of treating cancer or another proliferative disordercomprises administering a provided compound or composition thereof to amammal. In certain embodiments, the mammal is a human.

As used herein, the terms “inhibition of cancer” and “inhibition ofcancer cell proliferation” refer to the inhibition, or decrease in therate, of the growth, division, maturation or viability of cancer cells,and/or causing the death of cancer cells, individually or in aggregatewith other cancer cells, by cytotoxicity, nutrient depletion, or theinduction of apoptosis.

Examples of tissues containing cancerous cells whose proliferation isinhibited by the a provided compound or composition thereof describedherein and against which the methods described herein are useful includebut are not limited to breast, prostate, brain, blood, bone marrow,liver, pancreas, skin, kidney, colon, ovary, lung, testicle, penis,thyroid, parathyroid, pituitary, thymus, retina, uvea, conjunctiva,spleen, head, neck, trachea, gall bladder, rectum, salivary gland,adrenal gland, throat, esophagus, lymph nodes, sweat glands, sebaceousglands, muscle, heart, and stomach.

In some embodiments, the cancer treated by a provided compound orcomposition thereof is a melanoma, liposarcoma, lung cancer, breastcancer, prostate cancer, leukemia, kidney cancer, esophageal cancer,brain cancer, lymphoma or colon cancer. In certain embodiments, thecancer is a primary effusion lymphoma (PEL). In certain preferredembodiments, the cancer to be treated by a provided compound orcomposition thereof is one bearing an activated MAPK pathway. In someembodiments, the cancer bearing an activated MAPK pathway is a melanoma.In certain preferred embodiments, the cancer treated by a providedcompound or composition thereof is one associated with BRCA1 mutation.In an especially preferred embodiment, the cancer treated by a providedcompound or composition thereof is a triple negative breast cancer.

In certain embodiments, the diseases which can be treated by a providedcompound or composition thereof are neurological disorders. In someembodiments, the neurological disorder is Alzheimer's Disease,Parkinson's Disease, epilepsy, ischemia, Age Associated MemoryImpairment, Mild Cognitive Impairment, Friedreich's Ataxia,GLUT1-deficient epilepsy, Leprechaunism, Rabson-Mendenhall Syndrome,Coronary Arterial Bypass Graft dementia, anaesthesia-induced memoryloss, amyotrophic lateral sclerosis, glioma or Huntington's Disease.

In certain embodiments, the disease which can be treated by a providedcompound or composition thereof is an infectious disease. In someembodiments, the infectious disease is a viral infection. In someembodiments the viral infection is cytomegalovirus infection orinfluenza infection. In some embodiments, the infectious disease is afungal infection. In some embodiments, the infectious disease is abacterial infection.

Depending upon the particular condition, or disease, to be treated,additional therapeutic agents, which are normally administered to treatthat condition, may be administered in combination with a providedcompound or composition thereof. As used herein, additional therapeuticagents that are normally administered to treat a particular disease, orcondition, are known as “appropriate for the disease, or condition,being treated.”

In certain embodiments, a provided compound or composition thereof isadministered in combination with one or more additional antifungal(antimycotic) agents for the treatment of a fungal infection. In someembodiments, the one or more additional antifungal (antimycotic) agentsare selected from polyene antifungals (including but not limited toamphotericin B (as amphotericin B deoxycholate, amphotericin B lipidcomplex, or liposomal amphotericin B), candicidin, filipin, hamycin,natamycin, nystatin, and rimocidin), azole antifungals (including butnot limited to abafungin, albaconazole, bifonazole, butoconazole,clotrimazole, econazole, efinaconazole, epoxiconazole, fenticonazole,fluconazole, isavuconazole, isoconazole, itraconazole, ketoconazole,luliconazole, miconazole, omoconazole, oxiconazole, posaconazole,propiconazole, ravuconazole, sertaconazole, sulconazole, terconazole,tioconazole, and voriconazole), allylamines (including but not limitedto amorolfin, butenafine, naftifine, and terbinafine), echinocandins(including but not limited to anidulafungin, caspofungin, andmicafungin), benzoic acid, ciclopirox, flucytosine, griseofulvin,haloprogin, tolnaftate, undecylenic acid, and crystal violet.

In certain embodiments, a provided compound or composition thereof isadministered in combination with another inhibitor of ACC or antiobesityagent. In some embodiments, a provided compound or composition thereofis administered in combination with one or more other therapeuticagents. Such therapeutic agents include, but are not limited to agentssuch as orlistat (Xenical), CNS stimulants, Qsymia, or Belviq.

In certain embodiments, a provided compound or a composition thereof isadministered in combination with another anti-cancer, cytotoxin, orchemotherapeutic agent, to a patient in need thereof.

In certain embodiments, the anti-cancer or chemotherapeutic agents usedin combination with a provided compound or composition thereof include,but are not limited to, metformin, phenformin, buformin, imatinib,nilotinib, gefitinib, sunitinib, carfilzomib, salinosporamide A,retinoic acid, cisplatin, carboplatin, oxaliplatin, mechlorethamine,cyclophosphamide, chlorambucil, ifosfamide, azathioprine,mercaptopurine, doxifluridine, fluorouracil, gemcitabine, methotrexate,tioguanine, vincristine, vinblastine, vinorelbine, vindesine,podophyllotoxin, etoposide, teniposide, tafluposide, paclitaxel,docetaxel, irinotecan, topotecan, amsacrine, actinomycin, doxorubicin,daunorubicin, valrubicin, idarubicin, epirubicin, plicamycin, mitomycin,mitoxantrone, melphalan, busulfan, capecitabine, pemetrexed,epothilones, 13-cis-Retinoic Acid, 2-CdA, 2-Chlorodeoxyadenosine,5-Azacitidine, 5-Fluorouracil, 5-FU, 6-Mercaptopurine, 6-MP, 6-TG,6-Thioguanine, Abraxane, Accutane®, Actinomycin-D, Adriamycin®,Adrucil®, Afinitor®, Agrylin®, Ala-Cort®, Aldesleukin, Alemtuzumab,ALIMTA, Alitretinoin, Alkaban-AQ®, Alkeran®, All-transretinoic Acid,Alpha Interferon, Altretamine, Amethopterin, Amifostine,Aminoglutethimide, Anagrelide, Anandron®, Anastrozole,Arabinosylcytosine, Ara-C, Aranesp®, Aredia®, Arimidex®, Aromasin®,Arranon®, Arsenic Trioxide, Arzerra™, Asparaginase, ATRA, Avastin®,Azacitidine, BCG, BCNU, Bendamustine, Bevacizumab, Bexarotene, BEXXAR®,Bicalutamide, BiCNU, Blenoxane®, Bleomycin, Bortezomib, Busulfan,Busulfex®, C225, Calcium Leucovorin, Campath®, Camptosar®,Camptothecin-11, Capecitabine, Carac™, Carboplatin, Carmustine,Carmustine Wafer, Casodex®, CC-5013, CCI-779, CCNU, CDDP, CeeNU,Cerubidine®, Cetuximab, Chlorambucil, Citrovorum Factor, Cladribine,Cortisone, Cosmegen®, CPT-11, Cytadren®, Cytosar-U®, Cytoxan®,Dacarbazine, Dacogen, Dactinomycin, Darbepoetin Alfa, Dasatinib,Daunomycin, Daunorubicin Hydrochloride, Daunorubicin Liposomal,DaunoXome®, Decadron, Decitabine, Delta-Cortef®, Deltasone®, Denileukin,Diftitox, DepoCyt™, Dexamethasone, Dexamethasone Acetate, DexamethasoneSodium Phosphate, Dexasone, Dexrazoxane, DHAD, DIC, Diodex, Docetaxel,Doxil®, Doxorubicin, Doxorubicin Liposomal, Droxia™, DTIC, DTIC-Dome®,Duralone®, Efudex®, Eligard™, Ellence™, Eloxatin™, Elspar®, Emcyt®,Epirubicin, Epoetin Alfa, Erbitux, Erlotinib, Erwinia L-asparaginase,Estramustine, Ethyol, Etopophos®, Etoposide, Etoposide Phosphate,Eulexin®, Everolimus, Evista®, Exemestane, Fareston®, Faslodex®,Femara®, Filgrastim, Floxuridine, Fludara®, Fludarabine, Fluoroplex®,Fluorouracil, Fluorouracil (cream), Fluoxymesterone, Flutamide, FolinicAcid, FUDR®, Fulvestrant, G-CSF, Gefitinib, Gemcitabine, Gemtuzumab,ozogamicin, Gemzar Gleevec™, Gliadel® Wafer, GM-CSF, Goserelin,Granulocyte-Colony Stimulating Factor, Granulocyte Macrophage ColonyStimulating Factor, Halotestin®, Herceptin®, Hexadrol, Hexalen®,Hexamethylmelamine, HMM, Hycamtin®, Hydrea®, Hydrocort Acetate®,Hydrocortisone, Hydrocortisone Sodium Phosphate, Hydrocortisone SodiumSuccinate, Hydrocortone Phosphate, Hydroxyurea, Ibritumomab,Ibritumomab, Tiuxetan, Idamycin®, Idarubicin Ifex®, IFN-alpha,Ifosfamide, IL-11, IL-2, Imatinib mesylate, Imidazole Carboxamide,Interferon alfa, Interferon Alfa-2b (PEG Conjugate), Interleukin-2,Interleukin-11, Intron A® (interferon alfa-2b), Iressa®, Irinotecan,Isotretinoin, Ixabepilone, Ixempra™, Kidrolase®, Lanacort®, Lapatinib,L-asparaginase, LCR, Lenalidomide, Letrozole, Leucovorin, Leukeran,Leukine™, Leuprolide, Leurocristine, Leustatin™, Liposomal Ara-C, LiquidPred®, Lomustine, L-PAM, L-Sarcolysin, Lupron®, Lupron Depot®,Matulane®, Maxidex, Mechlorethamine, Mechlorethamine Hydrochloride,Medralone®, Medrol®, Megace®, Megestrol, Megestrol Acetate, Melphalan,Mercaptopurine, Mesna, Mesnex™, Methotrexate, Methotrexate Sodium,Methylprednisolone, Meticorten®, Mitomycin, Mitomycin-C, Mitoxantrone,M-Prednisol®, MTC, MTX, Mustargen®, Mustine, Mutamycin®, Myleran®,Mylocel™, Mylotarg®, Navelbine®, Nelarabine, Neosar®, Neulasta™,Neumega®, Neupogen®, Nexavar®, Nilandron®, Nilotinib, Nilutamide,Nipent®, Nitrogen Mustard, Novaldex®, Novantrone®, Nplate, Octreotide,Octreotide acetate, Ofatumumab, Oncospar®, Oncovin®, Ontak®, Onxal™,Oprelvekin, Orapred®, Orasone®, Oxaliplatin, Paclitaxel, PaclitaxelProtein-bound, Pamidronate, Panitumumab, Panretin®, Paraplatin®,Pazopanib, Pediapred®, PEG Interferon, Pegaspargase, Pegfilgrastim,PEG-INTRON™, PEG-L-asparaginase, PEMETREXED, Pentostatin, PhenylalanineMustard, Platinol®, Platinol-AQ®, Prednisolone, Prednisone, Prelone®,Procarbazine, PROCRIT®, Proleukin®, Prolifeprospan 20 with CarmustineImplant, Purinethol®, Raloxifene, Revlimid®, Rheumatrex®, Rituxan®,Rituximab, Roferon-A® (Interferon Alfa-2a), Romiplostim, Rubex®,Rubidomycin hydrochloride, Sandostatin®, Sandostatin LAR®, Sargramostim,Solu-Cortef®, Solu-Medrol®, Sorafenib, SPRYCEL™, STI-571, Streptozocin,SU11248, Sunitinib, Sutent®, Tamoxifen, Tarceva®, Targretin®, Tasigna®,Taxol®, Taxotere®, Temodar®, Temozolomide, Temsirolimus, Teniposide,TESPA, Thalidomide, Thalomid®, TheraCys®, Thioguanine, ThioguanineTabloid®, Thiophosphoamide, Thioplex®, Thiotepa, TICE®, Toposar®,Topotecan, Toremifene, Torisel®, Tositumomab, Trastuzumab, Treanda®,Tretinoin, Trexall™, Trisenox®, TSPA, TYKERB®, VCR, Vectibix™, Velban®,Velcade®, VePesid®, Vesanoid®, Viadur™, Vidaza®, Vinblastine,Vinblastine Sulfate, Vincasar Pfs®, Vincristine, Vinorelbine,Vinorelbine tartrate, VLB, VM-26, Vorinostat, Votrient, VP-16, Vumon®,Xeloda®, Zanosar®, Zevalin™, Zinecard®, Zoladex®, Zoledronic acid,Zolinza, Zometa®, or combinations of any of the above.

In certain embodiments, a provided compound or composition may beadministered together with a biguanide selected from metformin,phenformin, or buformin, to a patient in need thereof. In certainembodiments, the patient administered a combination of a providedcompound and a biguanide is suffering from a cancer, obesity, a liverdisease, diabetes or two or more of the above.

In some embodiments, a provided compound or composition may beadministered together alone or with one or more additional therapeuticagents for the treatment of acne vulgaris. In some embodiments, the oneor more additional therapeutic agents for the treatment of acne vulgarisare selected from topical anti-acne agents (e.g. retinoids, topicalantibiotics, benzoyl peroxides), or systemic anti-acne agents (e.g.hormonal therapies, oral antibiotics, isotretinoin). In someembodiments, the hormonal therapy is an oral contraceptive or anandrogen blocker. In some embodiments, the oral antibiotic isdoxycycline, minocycline, tetracycline, or erythromycin.

In some embodiments, a provided compound or composition may beadministered together alone or with one or more additional therapeuticagents for the treatment of seborrhea. In some embodiments, a providedcompound or composition may be administered together alone or with oneor more additional therapeutic agents for the treatment of seborrheicdermatitis. In some embodiments, a provided compound or composition maybe administered together alone or with one or more additionaltherapeutic agents for the treatment of seborrheic keratosis.

In certain embodiments, a combination of two or more therapeutic agentsmay be administered together with a provided compound. In certainembodiments, a combination of 3 or more therapeutic agents may beadministered with a provided compound.

Other examples of agents the compounds of this invention may also becombined with include, without limitation: vitamins and nutritionalsupplements, cancer vaccines, treatments for neutropenia (e.g. G-CSF,filgrastim, lenograstim), treatments for thrombocytopenia (e.g. bloodtransfusion, erythropoietin), PI3 kinase (PI3K) inhibitors, MEKinhibitors, AMPK activators, PCSK9 inhibitors, SREBP site 1 proteaseinhibitors, HMG CoA-reductase inhibitors, antiemetics (e.g. 5-HT3receptor antagonists, dopamine antagonists, NK1 receptor antagonists,histamine receptor antagonists, cannabinoids, benzodiazepines, oranticholinergics), treatments for Alzheimer's Disease such as Aricept®and Excelon®; treatments for Parkinson's Disease such asL-DOPA/carbidopa, entacapone, ropinrole, pramipexole, bromocriptine,pergolide, trihexephendyl, and amantadine; agents for treating MultipleSclerosis (MS) such as beta interferon (e.g., Avonex® and Rebif®),Copaxone®, and mitoxantrone; treatments for asthma such as albuterol andSingulair®; agents for treating schizophrenia such as zyprexa,risperdal, seroquel, and haloperidol; anti-inflammatory agents such ascorticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide,and sulfasalazine; immunomodulatory and immunosuppressive agents such ascyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferons,corticosteroids, cyclophophamide, azathioprine, and sulfasalazine;neurotrophic factors such as acetylcholinesterase inhibitors, MAOinhibitors, interferons, anticonvulsants, ion channel blockers,riluzole, and anti-Parkinsonian agents; agents for treatingcardiovascular disease such as beta-blockers, ACE inhibitors, diuretics,nitrates, calcium channel blockers, and statins, fibrates, cholesterolabsorption inhibitors, bile acid sequestrants, and niacin; agents fortreating liver disease such as corticosteroids, cholestyramine,interferons, and anti-viral agents; agents for treating blood disorderssuch as corticosteroids, anti-leukemic agents, and growth factors;agents for treating immunodeficiency disorders such as gamma globulin;and anti-diabetic agents such as biguanides (metformin, phenformin,buformin), thiazolidinediones (rosiglitazone, pioglitazone,troglitazone), sulfonylureas (tolbutamide, acetohexamide, tolazamide,chlorpropamide, glipizide, glyburide, glimepiride, gliclazide),meglitinides (repaglinide, nateglinide), alpha-glucosidase inhibitors(miglitol, acarbose), incretin mimetics (exenatide, liraglutide,taspoglutide), gastric inhibitory peptide analogs, DPP-4 inhibitors(vildagliptin, sitagliptin, saxagliptin, linagliptin, alogliptin),amylin analogs (pramlintide), and insulin and insulin analogs.

In certain embodiments, a provided compound, or a pharmaceuticallyacceptable composition thereof, are administered in combination withantisense agents, a monoclonal or polyclonal antibody or a siRNAtherapeutic.

In some embodiments, the present invention provides a method oftreating, stabilizing or lessening the severity or progression of anon-alcoholic fatty liver disease (NAFLD), comprising administering to apatient in need thereof a provided compound, or a pharmaceuticallyacceptable composition thereof, in combination with one or moreadditional therapeutic agents. In certain embodiments, the one or moreadditional therapeutic agents are independently selected from the groupconsisting of angiotensin II receptor antagonists, angiotensinconverting enzyme (ACE) inhibitors, caspase inhibitors, cathepsin Binhibitors, CCR2 chemokine antagonists, CCR5 chemokine antagonists,chloride channel stimulators, cholesterol solubilizers, diacylglycerolO-acyltransferase 1 (DGAT1) inhibitors, dipeptidyl peptidase IV (DPPIV)inhibitors, farnesoid X receptor (FXR) agonists, FXR/TGR5 dual agonists,galectin-3 inhibitors, glucagon-like peptide 1 (GLP1) agonists,glutathione precursors, hepatitis C virus NS3 protease inhibitors, HMGCoA reductase inhibitors, 11β-hydroxysteroid dehydrogenase (11β-HSD1)inhibitors, IL-1β antagonists, IL-6 antagonists, IL-10 agonists, IL-17antagonists, ileal sodium bile acid cotransporter inhibitors, leptinanalogs, 5-lipoxygenase inhibitors, LPL gene stimulators, lysyl oxidasehomolog 2 (LOXL2) inhibitors, PDE3 inhibitors, PDE4 inhibitors,phospholipase C (PLC) inhibitors, PPARα agonists, PPARγ agonists, PPARδagonists, Rho associated protein kinase 2 (ROCK2) inhibitors, sodiumglucose transporter-2 (SGLT2) inhibitors, stearoyl CoA desaturase-1inhibitors, thyroid hormone receptor β agonists, tumor necrosis factor α(TNFα) ligand inhibitors, transglutaminase inhibitors, transglutaminaseinhibitor precursors, PTP1b inhibitors, and ASK1 inhibitors.

In some embodiments, a provided compound, or a pharmaceuticallyacceptable composition thereof, is administered in combination with oneor more additional therapeutic agents, wherein at least one of theadditional therapeutic agents is an angiotensin II receptor antagonist.

In some embodiments, a provided compound, or a pharmaceuticallyacceptable composition thereof, is administered in combination with oneor more additional therapeutic agents, wherein at least one of theadditional therapeutic agents is an angiotensin converting enzyme (ACE)inhibitor. In some embodiments, the ACE inhibitor is enalapril.

In some embodiments, a provided compound, or a pharmaceuticallyacceptable composition thereof, is administered in combination with oneor more additional therapeutic agents, wherein at least one of theadditional therapeutic agents is a caspase inhibitor. In someembodiments the caspase inhibitor is emricasan.

In some embodiments, a provided compound, or a pharmaceuticallyacceptable composition thereof, is administered in combination with oneor more additional therapeutic agents, wherein at least one of theadditional therapeutic agents is a cathepsin B inhibitor. In someembodiments the cathepsin B inhibitor is a mixed cathepsin B/hepatitis Cvirus NS3 protease inhibitor. In some embodiments, the mixed cathepsinB/hepatitis C virus NS3 protease inhibitor is VBY-376.

In some embodiments, a provided compound, or a pharmaceuticallyacceptable composition thereof, is administered in combination with oneor more additional therapeutic agents, wherein at least one of theadditional therapeutic agents is a CCR2 chemokine antagonist. In someembodiments, the additional therapeutic agent is a mixed CCR2/CCR5chemokine antagonist. In some embodiments, the mixed CCR2/CCR5 chemokineantagonist is cenicriviroc.

In some embodiments, a provided compound, or a pharmaceuticallyacceptable composition thereof, is administered in combination with oneor more additional therapeutic agents, wherein at least one of theadditional therapeutic agents is a CCR5 chemokine antagonist.

In some embodiments, a provided compound, or a pharmaceuticallyacceptable composition thereof, is administered in combination with oneor more additional therapeutic agents, wherein at least one of theadditional therapeutic agents is a chloride channel stimulator. In someembodiments, the chloride channel stimulator is cobiprostone.

In some embodiments, a provided compound, or a pharmaceuticallyacceptable composition thereof, is administered in combination with oneor more additional therapeutic agents, wherein at least one of theadditional therapeutic agents is a cholesterol solubilizer.

In some embodiments, a provided compound, or a pharmaceuticallyacceptable composition thereof, is administered in combination with oneor more additional therapeutic agents, wherein at least one of theadditional therapeutic agents is a diacylglycerol O-acyltransferase 1(DGAT1) inhibitor. In some embodiments, the DGAT1 inhibitor is LCQ908.

In some embodiments, a provided compound, or a pharmaceuticallyacceptable composition thereof, is administered in combination with oneor more additional therapeutic agents, wherein at least one of theadditional therapeutic agents is a dipeptidyl peptidase IV (DPPIV)inhibitor. In some embodiments, the DPPIV inhibitor is linagliptin.

In some embodiments, a provided compound, or a pharmaceuticallyacceptable composition thereof, is administered in combination with oneor more additional therapeutic agents, wherein at least one of theadditional therapeutic agents is a farnesoid X receptor (FXR) agonist.In some embodiments, the FXR agonist is INT-747 (obeticholic acid). Insome embodiments, the FXR agonist is PX-102.

In some embodiments, a provided compound, or a pharmaceuticallyacceptable composition thereof, is administered in combination with oneor more additional therapeutic agents, wherein at least one of theadditional therapeutic agents is an FXR/TGR5 dual agonist. In someembodiments, the FXR/TGR5 dual agonist is INT-767.

In some embodiments, a provided compound, or a pharmaceuticallyacceptable composition thereof, is administered in combination with oneor more additional therapeutic agents, wherein at least one of theadditional therapeutic agents is a galectin-3 inhibitor. In someembodiments, the galectin-3 inhibitor is GR-MD-02.

In some embodiments, a provided compound, or a pharmaceuticallyacceptable composition thereof, is administered in combination with oneor more additional therapeutic agents, wherein at least one of theadditional therapeutic agents is a glucagon-like peptide 1 (GLP1)agonist. In some embodiments, the GLP1 agonist is liraglutide. In someembodiments, the GLP1 agonist is exenatide.

In some embodiments, a provided compound, or a pharmaceuticallyacceptable composition thereof, is administered in combination with oneor more additional therapeutic agents, wherein at least one of theadditional therapeutic agents is a glutathione precursor.

In some embodiments, a provided compound, or a pharmaceuticallyacceptable composition thereof, is administered in combination with oneor more additional therapeutic agents, wherein at least one of theadditional therapeutic agents is a hepatitis C virus NS3 proteaseinhibitor. In some embodiments the hepatitis C virus NS3 proteaseinhibitor is a mixed cathepsin B/hepatitis C virus NS3 proteaseinhibitor. In some embodiments, the mixed cathepsin B/hepatitis C virusNS3 protease inhibitor is VBY-376.

In some embodiments, a provided compound, or a pharmaceuticallyacceptable composition thereof, is administered in combination with oneor more additional therapeutic agents, wherein at least one of theadditional therapeutic agents is an HMG CoA reductase inhibitor. In someembodiments, the HMG-CoA reductase inhibitor is a statin. In someembodiments, the HMG-CoA reductase inhibitor is atorvastatin.

In some embodiments, a provided compound, or a pharmaceuticallyacceptable composition thereof, is administered in combination with oneor more additional therapeutic agents, wherein at least one of theadditional therapeutic agents is an 11β-hydroxysteroid dehydrogenase(11β-HSD1) inhibitor. In some embodiments, the 11β-HSD1 inhibitor isRO5093151.

In some embodiments, a provided compound, or a pharmaceuticallyacceptable composition thereof, is administered in combination with oneor more additional therapeutic agents, wherein at least one of theadditional therapeutic agents is an IL-1β antagonist.

In some embodiments, a provided compound, or a pharmaceuticallyacceptable composition thereof, is administered in combination with oneor more additional therapeutic agents, wherein at least one of theadditional therapeutic agents is an IL-6 antagonist. In someembodiments, the IL-6 antagonist is a mixed IL-6/IL-13/TNFα ligandinhibitor. In some embodiments, the mixed IL-6/IL-1β/TNFα ligandinhibitor is BLX-1002.

In some embodiments, a provided compound, or a pharmaceuticallyacceptable composition thereof, is administered in combination with oneor more additional therapeutic agents, wherein at least one of theadditional therapeutic agents is an IL-10 agonist. In some embodiments,the IL-10 agonist is peg-ilodecakin.

In some embodiments, a provided compound, or a pharmaceuticallyacceptable composition thereof, is administered in combination with oneor more additional therapeutic agents, wherein at least one of theadditional therapeutic agents is an IL-17 antagonist. In someembodiments, the IL-17 antagonist is KD-025.

In some embodiments, a provided compound, or a pharmaceuticallyacceptable composition thereof, is administered in combination with oneor more additional therapeutic agents, wherein at least one of theadditional therapeutic agents is an ileal sodium bile acid cotransporterinhibitor. In some embodiments, the ileal sodium bile acid cotransporterinhibitor is SHP-626.

In some embodiments, a provided compound, or a pharmaceuticallyacceptable composition thereof, is administered in combination with oneor more additional therapeutic agents, wherein at least one of theadditional therapeutic agents is a leptin analog. In some embodimentsthe leptin analog is metreleptin.

In some embodiments, a provided compound, or a pharmaceuticallyacceptable composition thereof, is administered in combination with oneor more additional therapeutic agents, wherein at least one of theadditional therapeutic agents is a 5-lipoxygenase inhibitor. In someembodiments, the 5-lipoxygenase inhibitor is a mixed5-lipoxygenase/PDE3/PDE4/PLC inhibitor. In some embodiments, the mixed5-lipoxygenase/PDE3/PDE4/PLC inhibitor is tipelukast.

In some embodiments, a provided compound, or a pharmaceuticallyacceptable composition thereof, is administered in combination with oneor more additional therapeutic agents, wherein at least one of theadditional therapeutic agents is a LPL gene stimulator. In someembodiments the LPL gene stimulator is alipogene tiparvovec.

In some embodiments, a provided compound, or a pharmaceuticallyacceptable composition thereof, is administered in combination with oneor more additional therapeutic agents, wherein at least one of theadditional therapeutic agents is a lysyl oxidase homolog 2 (LOXL2)inhibitor. In some embodiments, the LOXL2 inhibitor is an anti-LOXL2antibody. In some embodiments, the anti-LOXL2 antibody is GS-6624.

In some embodiments, a provided compound, or a pharmaceuticallyacceptable composition thereof, is administered in combination with oneor more additional therapeutic agents, wherein at least one of theadditional therapeutic agents is a PDE3 inhibitor. In some embodiments,the PDE3 inhibitor is a mixed 5-lipoxygenase/PDE3/PDE4/PLC inhibitor. Insome embodiments, the mixed 5-lipoxygenase/PDE3/PDE4/PLC inhibitor istipelukast.

In some embodiments, a provided compound, or a pharmaceuticallyacceptable composition thereof, is administered in combination with oneor more additional therapeutic agents, wherein at least one of theadditional therapeutic agents is a PDE4 inhibitor. In some embodiments,the PDE4 inhibitor is ASP-9831. In some embodiments, the PDE4 inhibitoris a mixed 5-lipoxygenase/PDE3/PDE4/PLC inhibitor. In some embodiments,the mixed 5-lipoxygenase/PDE3/PDE4/PLC inhibitor is tipelukast.

In some embodiments, a provided compound, or a pharmaceuticallyacceptable composition thereof, is administered in combination with oneor more additional therapeutic agents, wherein at least one of theadditional therapeutic agents is a phospholipase C (PLC) inhibitor. Insome embodiments, the PLC inhibitor is a mixed5-lipoxygenase/PDE3/PDE4/PLC inhibitor. In some embodiments, the mixed5-lipoxygenase/PDE3/PDE4/PLC inhibitor is tipelukast.

In some embodiments, a provided compound, or a pharmaceuticallyacceptable composition thereof, is administered in combination with oneor more additional therapeutic agents, wherein at least one of theadditional therapeutic agents is a PPARα agonist. In some embodimentsthe PPARα agonist is a mixed PPARα/δ agonist. In some embodiments, themixed PPARα/δ agonist is GFT505.

In some embodiments, a provided compound, or a pharmaceuticallyacceptable composition thereof, is administered in combination with oneor more additional therapeutic agents, wherein at least one of theadditional therapeutic agents is a PPARγ agonist. In some embodiments,the PPARγ agonist is pioglitazone.

In some embodiments, a provided compound, or a pharmaceuticallyacceptable composition thereof, is administered in combination with oneor more additional therapeutic agents, wherein at least one of theadditional therapeutic agents is a PPARγ agonist.

In some embodiments, a provided compound, or a pharmaceuticallyacceptable composition thereof, is administered in combination with oneor more additional therapeutic agents, wherein at least one of theadditional therapeutic agents is a Rho associated protein kinase 2(ROCK2) inhibitor. In some embodiments the ROCK2 inhibitor is KD-025.

In some embodiments, a provided compound, or a pharmaceuticallyacceptable composition thereof, is administered in combination with oneor more additional therapeutic agents, wherein at least one of theadditional therapeutic agents is a sodium glucose transporter-2 (SGLT2)inhibitor. In some embodiments, the SGLT2 inhibitor is remogliflozinetabonate.

In some embodiments, a provided compound, or a pharmaceuticallyacceptable composition thereof, is administered in combination with oneor more additional therapeutic agents, wherein at least one of theadditional therapeutic agents is a stearoyl CoA desaturase-1 inhibitor.In some embodiments, the stearoyl CoA desaturase-1 inhibitor isaramchol. In some embodiments, the stearoyl CoA desaturase-1 inhibitoris CVT-12805.

In some embodiments, a provided compound, or a pharmaceuticallyacceptable composition thereof, is administered in combination with oneor more additional therapeutic agents, wherein at least one of theadditional therapeutic agents is a thyroid hormone receptor (3 agonist.In some embodiments the thyroid hormone receptor β agonist is MGL-3196.

In some embodiments, a provided compound, or a pharmaceuticallyacceptable composition thereof, is administered in combination with oneor more additional therapeutic agents, wherein at least one of theadditional therapeutic agents is a tumor necrosis factor α (TNFα) ligandinhibitor.

In some embodiments, a provided compound, or a pharmaceuticallyacceptable composition thereof, is administered in combination with oneor more additional therapeutic agents, wherein at least one of theadditional therapeutic agents is a transglutaminase inhibitor. In someembodiments, the transglutaminase inhibitor precursor is mercaptamine.

In some embodiments, a provided compound, or a pharmaceuticallyacceptable composition thereof, is administered in combination with oneor more additional therapeutic agents, wherein at least one of theadditional therapeutic agents is a transglutaminase inhibitor precursor.

In some embodiments, a provided compound, or a pharmaceuticallyacceptable composition thereof, is administered in combination with oneor more additional therapeutic agents, wherein at least one of theadditional therapeutic agents is a PTP1b inhibitor. In some embodiments,the PTP b inhibitor is A119505, A220435, A321842, CPT633, ISIS-404173,JTT-551, MX-7014, MX-7091, MX-7102, NNC-521246, OTX-001, OTX-002, orTTP814.

In some embodiments, a provided compound, or a pharmaceuticallyacceptable composition thereof, is administered in combination with oneor more additional therapeutic agents, wherein at least one of theadditional therapeutic agents is an ASK1 inhibitor. In some embodiments,the ASK1 inhibitor is GS-4977 (also known as selonsertib).

In some embodiments, the one or more additional therapeutic agents areindependently selected from acetylsalicylic acid, alipogene tiparvovec,aramchol, atorvastatin, BLX-1002, cenicriviroc, cobiprostone,colesevelam, emricasan, enalapril, GFT-505, GR-MD-02,hydrochlorothiazide, icosapent ethyl ester (ethyl eicosapentaenoicacid), IMM-124E, KD-025, linagliptin, liraglutide, mercaptamine,MGL-3196, obeticholic acid, olesoxime, peg-ilodecakin, pioglitazone,PX-102, remogliflozin etabonate, SHP-626, solithromycin, tipelukast,TRX-318, ursodeoxycholic acid, and VBY-376.

In some embodiments, one of the one or more additional therapeuticagents is acetylsalicylic acid. In some embodiments, one of the one ormore additional therapeutic agents is alipogene tiparvovec. In someembodiments, one of the one or more additional therapeutic agents isaramchol. In some embodiments, one of the one or more additionaltherapeutic agents is atorvastatin. In some embodiments, one of the oneor more additional therapeutic agents is BLX-1002. In some embodiments,one of the one or more additional therapeutic agents is cenicriviroc. Insome embodiments, one of the one or more additional therapeutic agentsis cobiprostone. In some embodiments, one of the one or more additionaltherapeutic agents is colesevelam. In some embodiments, one of the oneor more additional therapeutic agents is emricasan. In some embodiments,one of the one or more additional therapeutic agents is enalapril. Insome embodiments, one of the one or more additional therapeutic agentsis GFT-505. In some embodiments, one of the one or more additionaltherapeutic agents is GR-MD-02. In some embodiments, one of the one ormore additional therapeutic agents is hydrochlorothiazide. In someembodiments, one of the one or more additional therapeutic agents isicosapent ethyl ester (ethyl eicosapentaenoic acid). In someembodiments, one of the one or more additional therapeutic agents isIMM-124E. In some embodiments, one of the one or more additionaltherapeutic agents is KD-025. In some embodiments, one of the one ormore additional therapeutic agents is linagliptin. In some embodiments,one of the one or more additional therapeutic agents is liraglutide. Insome embodiments, one of the one or more additional therapeutic agentsis mercaptamine. In some embodiments, one of the one or more additionaltherapeutic agents is MGL-3196. In some embodiments, one of the one ormore additional therapeutic agents is obeticholic acid. In someembodiments, one of the one or more additional therapeutic agents isolesoxime. In some embodiments, one of the one or more additionaltherapeutic agents is peg-ilodecakin. In some embodiments, one of theone or more additional therapeutic agents is pioglitazone. In someembodiments, one of the one or more additional therapeutic agents isPX-102. In some embodiments, one of the one or more additionaltherapeutic agents is remogliflozin etabonate. In some embodiments, oneof the one or more additional therapeutic agents is SHP-626. In someembodiments, one of the one or more additional therapeutic agents issolithromycin. In some embodiments, one of the one or more additionaltherapeutic agents is tipelukast. In some embodiments, one of the one ormore additional therapeutic agents is TRX-318. In some embodiments, oneof the one or more additional therapeutic agents is ursodeoxycholicacid. In some embodiments, one of the one or more additional therapeuticagents is and VBY-376.

In some embodiments, at least one of the one or more additionaltherapeutic agents is an anti-diabetic agent. In some embodiments, theanti-diabetic agent is an adenosine A₁ receptor agonist (e.g. adenosine,CCPA, CVT-3619, GR-190718), an adenosine A2 receptor antagonist(istradefylline, SCH-58261), an aldose reductase inhibitor, an α-amylaseinhibitor (e.g. tendamistat, treastatin, AL-3688), an α-glucosidaseinhibitor (e.g. acarbose, camiglibose, diposine, emiglitate, miglitol,pradimicin-Q, sarbostatin, voglibose), an amylin analog (e.g. AC164209and pramlintide), an AMPK activator, a 33-adrenergic agonist (e.g.amibegron, AZ-40140, CL-316,243, KRP-204, L-742,791, L-796,568,LY-368,842, LY-377,604, mirabegron, Ro 40-2148, solabegron, SWR-0342SA),a 0-ketoacyl-acyl carrier protein synthase inhibitor, a biguanide (e.g.metformin, buformin, phenformin), a carnitine palmitoyl transferaseinhibitor, a DGAT-2 inhibitor, a DPP-4 inhibitor (e.g. alogliptin,anagliptin, dutogliptin, gemigliptin, linagliptin, omarigliptin,saxagliptin, sitagliptin, teneligliptin, trelagliptin, andvildagliptin), an ERN1 inhibitor, a fatty acid oxidation inhibitor, afatty acid synthase (FAS) inhibitor, an FGF21 derivative, a fructose1,6-diphosphatase inhibitor, a GLP1 agonist (e.g. albiglutide,dulaglutide, exenatide, liraglutide, lixisenatide, taspoglutide), aglucagon receptor modulator, a mixed glucagon receptor/GLP-1 agonist(e.g. MAR-701, ZP2929), a glucokinase inhibitor (e.g. TTP-399, TTP-355,TTP-547, AZD1656, ARRY403, MK-0599, TAK-329, AZD5658, and GKM-001), aglycogen phosphorylase inhibitor (e.g. GSK1362885), a GSK-3 inhibitor, aGPR119 agonist (e.g. MBX-2982, GSK1292263, APD597, PSN821), a GPBAR1(TGR5) agonist (e.g. INT-777, XL-475), a GPR39 modulator, a GPR40agonist (e.g. TAK-875), a GPR41 modulator, a GPR43 modulator, a GPR81modulator, a GPR120 agonist, an HSL inhibitor, an IκB inhibitor, anILI-beta modulator, insulin or an insulin analog (including, but notlimited to, oral, inhaled or injectable formulations thereof),insulin-like growth factor (IGF-1) or an analog thereof, an insulinsecretagogue, a JNK inhibitor (e.g. CC-359), a kappa opioid receptormodulator, LY3084077, a Kv1.3 inhibitor (e.g. ChTX, clofazmine,WIN-173173), a MAP4K4 inhibitor, an MC₁ or MC₄ agonist (e.g.afamelanotide, BMS-470539, bremelanotide, Melanotan II, PF-00446687,PL-6983, setmelanotide, and THIQ), a meglitinide (e.g. repaglinide,nateglinide, mitiglinide), a mineralocorticoid receptor inhibitor, amonoacylglycerol O-acyltransferase inhibitor, an NF-κB inhibitor, anicotinic acid receptor (HM74A) activator, a PDE-10 inhibitor, a PDHK2inhibitor, a PDHK4 inhibitor, a PKC (including PKC-alpha, PKC-beta, andPKC-gamma) inhibitor, a PPARα/γ dual agonist, a PTP1b inhibitor (e.g.trodusquemine), a retinol binding protein 4 inhibitor, a serinepalmitoyl transferase inhibitor, an SGLT1 inhibitor (e.g. GSK1614235), aSIRT-1 inhibitor (e.g. resveratrol, GSK2245840, GSK184072), asomatostatin receptor inhibitor, a sulfonylurea (e.g. acetohexamide,chlorpropamide, diabinese, glibenclamide, glipizide, glyburide,blimipiride, gliclazide, glipentide, gliquidone, glisolamide,tolazamide, tolbutamide), a thiazolidinedione (e.g. ciglitazone,darglitazone, englitazone, lobeglitazone, MSDC-0602, netoglitazone,pioglitazone, rivoglitazone, rosiglitazone, and troglitazone), a TORC2inhibitor, a urotensin II receptor agonist, a vasopressin agonist (e.g.DDAVP, WAY-141608), or a VPAC2 receptor agonist.

In some embodiments, at least one of the one or more additionaltherapeutic agents is an anti-antiobesity agent. In some embodiments,the anti-obesity agent is an apoB-MTP inhibitor (e.g. dirlotapide,JTT130, SLX4090, usistapide), a 33-adrenergic agonist (e.g. amibegron,AZ-40140, CL-316,243, KRP-204, L-742,791, L-796,568, LY-368,842,LY-377,604, mirabegron, Ro 40-2148, solabegron, SWR-0342SA), a bombesinreceptor agonist, a BRS3 modulator, a CB1 receptor antagonist or inverseagonist, a CCKA agonist, ciliary neurotrophic factor (CNTF) or analogthereof (e.g. axokine, NT-501), Contrave™ (buproprion/naltrexone), adopamine receptor agonist (e.g. bromocriptine), an 110-hydroxysteroiddehydrogenase (11β-HSD1) inhibitor, Empatic™ (pramlintide/metreleptin),a 5-HT2c agonist (e.g. lorcaserin), a galanin antagonist, a ghrelinagonist or antagonist, a GLP1 agonist (e.g. albiglutide, dulaglutide,exenatide, liraglutide, lixisenatide, taspoglutide), a mixed glucagonreceptor/GLP-1 agonist (e.g. MAR-701, ZP2929), an H3 antagonist orinverse agonist, a human agouti-related protein (AGRP) inhibitor, leptinor an analog thereof (e.g. metreleptin), a lipase inhibitor (e.g.tetrahydrolipstatin), an MC₁ or MC₄ agonist (e.g. afamelanotide,BMS-470539, bremelanotide, Melanotan II, PF-00446687, PL-6983,setmelanotide, and THIQ), a melanocyte-stimulating hormone or analogthereof, a MetAp2 inhibitor (e.g. ZGN-433), a monoamine reuptakeinhibitor (e.g. buproprion, sibutramine, phentermine, tesofensine), aneuromedin U receptor agonist, an NPY antagonist (e.g. velneperit), anopioid receptor antagonist (e.g. naltrexone), an orexin receptorantagonist (e.g. almorexant, lemborexant, SB-334,867, SB-408,124,SB-649,868, suvorexant), oxyntomodulin or an analog thereof, PYY or ananalog thereof (e.g. PYY₁₋₃₆, PYY₃₋₃₆), Qsymia™(phentermine/topiramate), an RXR-alpha modulator, a stearoyl-CoAdesaturase (SCD-1) inhibitor, or a sympathomimetic agent.

In some embodiments, at least one of the one or more additionaltherapeutic agents is a lipid lowering agent. In some embodiments, thelipid lowering agent is an acyl coenzyme A cholesterol acyl transferase(ACAT) inhibitor, a bile acid reabsorption inhibitor, a cholesterolester transfer protein (CETP) inhibitor, a 5-LOX inhibitor (e.g. BAY X1005), a FLAP inhibitor (e.g. AM-679), an HMG CoA synthase inhibitor, alipoprotein synthesis inhibitor, a low-density lipoprotein receptorinducer, an LXR receptor modulator, a microsomal triglyceride transportinhibitor, niacin, a platelet aggregation inhibitor, a renin-angiotensinsystem inhibitor, a squalene epoxidase inhibitor, a squalene synthetaseinhibitor, or a triglyceride synthesis inhibitor.

In some embodiments, at least one of the one or more additionaltherapeutic agents is an agent for treating a metabolic disorder. Insome embodiments, the agent for treating a metabolic disorder is an ABCtransporter activator, ACT-434964 (Actelion), an ANG-5 inhibitor, anangiotensin II antagonist (e.g. MC4262), CCX-872, DUR-928 (Durect),ESP41091, F-652 (Generon), an FGF21 agonist (e.g. BMS-986036),fomepizole (Raptor), an FXR agonist, FXR/TGR5 dual agonist (e.g.INT-767), a ghrelin antagonist (e.g. TZP-301), a glucosylceramidesynthase inhibitor, a GPR17 modulator, a GPR119 agonist, IG-MD-014(Indigene), IMM-124E (Immuron), a lysosome pathway modulator (e.g.CAT5000), a melanin-concentrating hormone receptor 1 antagonist (e.g.KI-1361-17), an MCL1 inhibitor (e.g. CMPX-1023), an mTORC1 inhibitor, anNaCT (e.g. SLC13A5) inhibitor, a NHE3 inhibitor (e.g. RDX-011,tenapanor), NP003 (Neuraltus), PBI-4050 (ProMetic), a proteostasisregulator (e.g. PTI-130, PTI-428, PTI-C1811), PS248288(Pharmacopeia/Merck), PX-102 (Phenex), RG7410. RG7652, a ROCK inhibitor,SBC-104 (Synageva BioPharma), SPX-100 (Spherix), a stearoyl CoAdesaturase inhibitor (e.g. CVT-12805), TRC 150094 (Torrent), or ZYH7(Zydus Cadila).

In some embodiments, at least one of the one or more additionaltherapeutic agents is an agent for treating steatosis. In someembodiments, the agent for treating steatosis is an adiponectin analog(e.g. PX 811013), aramchol (Galmed), an ASK1 inhibitor (e.g. GS-4977,GS-4997), AZD4076 (AstraZeneca), a bile acid sequestrant (e.g.obeticholic acid), BL-1060 (Galmed), BMS986171 (Bristol-Myers Squibb), aCCR5/CCR2 antagonist (e.g. cenicriviroc), cannabidiol, CER-209(Cerenis), a cysteamine analog (e.g. RP-103, RP-104), DS102 (DSBiopharma), EGS21 (Enzo), elafibranor (Genfit), emricasan (Idun), ethyleicosapentaenoic acid (Mochida), an FXR agonist, a GPBAR1 agonist (e.g.RDX009), GR-MD-02 (Galectin Therapeutics), leucine/sildenafil/metformin(NuSirt), LCQ908 (Novartis), LJN452 (Novartis), a LOXL2 inhibitor (e.g.simtuzumab), MAT-8800 (Matinas), MB-10866 (Metabasis), an miR-103/107inhibitor (e.g. RG-125), MK-4074 (Merck & Co.), nalmefene (TaiwanJ),nivocasan (Gilead), NGM-282 (NGM Biopharmaceuticals), an omega-3carboxylic acid or mixture of the same (e.g. Epanova™), PX-102 (Phenex),PX-104 (Phenex), remogliflozin etabonate (Kissei), saroglitazar(Zydus-Cadila), SAR-548304 (sanofi-aventis), tipelukast (Kyorin),ursodeoxycholic acid, VK2809 (Viking), or XL335 (Exelixis).

In some embodiments, at least one of the one or more additionaltherapeutic agents is an agent for treating inflammation. In someembodiments, the agent for treating inflammation reduces thedifferentiation or activation of T_(h)17 cells. In some embodiments, theagent for treating inflammation is a caspase inhibitor (e.g. emricasan),a TGF-β inhibitor, an IL-1β inhibitor, an IL-6 inhibitor, an L-17inhibitor, an IL-17a inhibitor, an IL-17F inhibitor, an L-21 inhibitor,an IL-23 inhibitor (e.g. guselkumab), IMM-124E, a RORγt inhibitor (e.g.JTE-151) a RORα inhibitor, solithromycin (Cempra), or a vascularadhesion protein-1 inhibitor (e.g. PXS-4728A).

In some embodiments, at least one of the one or more additionaltherapeutic agents is an agent for treating fibrosis. In someembodiments, the agent for treating fibrosis is cenicriviroc(Tobira/Takeda), CNX-014/023/024/025 (Connexios), an endothelinantagonist (e.g. A192621, ambrisentan, atracentan, bosentan, BQ-123,BQ-788, macitentan, sitaxentan, tezosentan, zibotentan), etanercept,evitar (AdeTherapeutics), a fibroblast growth factor inhibitor, agalectin-3 inhibitor, imatinib, IVA337 (Inventiva), N-acetylcysteine,nintedanib, pirfenidone, RG6069 (Roche), SP20102 (Sarfez), tipelukast(Kyorin), or XOMA 089 (Xoma).

In some embodiments, the non-alcoholic fatty liver disease is steatosis.In some embodiments, the non-alcoholic fatty liver disease isnon-alcoholic steatohepatitis (NASH). In some embodiments, thenon-alcoholic fatty liver disease is liver fibrosis caused by NASH. Insome embodiments, the non-alcoholic fatty liver disease is livercirrhosis caused by NASH. In some embodiments, the non-alcoholic fattyliver disease is hepatocellular carcinoma (HCC) caused by NASH.

Those additional agents may be administered separately from a providedcompound or composition thereof, as part of a multiple dosage regimen.Alternatively, those agents may be part of a single dosage form, mixedtogether with a provided compound in a single composition. Ifadministered as part of a multiple dosage regime, the two active agentsmay be submitted simultaneously, sequentially or within a period of timefrom one another, normally within five hours from one another.

As used herein, the term “combination,” “combined,” “in conjunction” andrelated terms refers to the simultaneous or sequential administration oftherapeutic agents in accordance with this invention. For example, aprovided compound may be administered with another therapeutic agentsimultaneously or sequentially in separate unit dosage forms or togetherin a single unit dosage form. Accordingly, the present inventionprovides a single unit dosage form comprising a provided compound, anadditional therapeutic agent, and a pharmaceutically acceptable carrier,adjuvant, or vehicle.

The amount of both, a provided compound and additional therapeutic agent(in those compositions which comprise an additional therapeutic agent asdescribed above) that may be combined with the carrier materials toproduce a single dosage form will vary depending upon the host treatedand the particular mode of administration. Preferably, compositions ofthis invention should be formulated so that a dosage of between 0.01-100mg/kg body weight/day of a provided compound can be administered.

In those compositions which comprise an additional therapeutic agent,that additional therapeutic agent and a provided compound may actsynergistically. Therefore, the amount of additional therapeutic agentin such compositions will be less than that required in a monotherapyutilizing only that therapeutic agent. In such compositions a dosage ofbetween 0.01-100 μg/kg body weight/day of the additional therapeuticagent can be administered.

The amount of additional therapeutic agent present in a compositioncomprising a provided compound will be no more than the amount thatwould normally be administered in a composition comprising thattherapeutic agent as the only active agent. Preferably the amount ofadditional therapeutic agent in a provided composition will range fromabout 50% to 100% of the amount normally present in a compositioncomprising that agent as the only therapeutically active agent.

EXEMPLIFICATION

As depicted in the Examples below, in certain exemplary embodiments,compounds and solid forms are prepared according to the precedinggeneral procedures. It will be appreciated that, although the generalmethods depict the synthesis of certain compounds of the presentinvention, the following methods, and other methods known to one ofordinary skill in the art, can be applied to all compounds andsubclasses and species of each of these compounds, as described herein.

Experimental Procedures

As used herein, “V”=volumes, “v/w”=volume/weight ratio,“v/v”=volume/volume ratio, and “w/w”=weight/weight ratio.

Example 1 Production of Amorphous Compound 1

1 gram of Compound 1, prepared according to the method described in US2013/0123231 A1, was completely dissolved in 10 mL dichloromethane. Thedichloromethane solution was evaporated rapidly under vacuum at 40° C.,resulting in amorphous Compound 1 having the XRPD pattern depicted inFIG. 18.

Example 2 Production of Form I of Compound 1

50 milligrams of amorphous Compound 1, prepared according to the methodof Example 1, was slurried in acetone and subjected to temperaturecycling from 40° C. to 25° C., in 4 h cycles for 72 h. Solid Form I ofCompound 1 was collected by filtration. Form I was determined to be anneat polymorph of Compound 1. Form I was determined to have poor aqueoussolubility at pH 5.5 and below (<10 μg/mL), with a logD value of 1.06 atpH 7.4.

The DSC curve of Form I of Compound 1 (FIG. 3A and FIG. 3B) indicates anendothermic transition with onset at about 189-193° C. attributed to amelt. The TGA curve of Form I of Compound 1 shows no significant weightloss up at about 150° C., indicating an unsolvated phase. The moisturesorption curve of Form I of Compound 1 also indicates that Form I isslightly hygroscopic showing around a 0.45% weight gain at about 95% RH.An XRPD analysis of the sample after the DVS experiment shows that thematerial had not changed forms.

Single crystals of Form I were obtained from an attempted salt formationexperiment. 0.5 mL Methyl ethyl ketone (MEK) was added to 40.5milligrams Compound 1 to form a suspension. In a separate vial, 10.2milligrams of L-proline was dissolved in 0.1 mL H₂O and the solution wasadded to the Compound 1 suspension. The sample was slurried at about 60°C. for about 5 days and formed a golden yellow solution. The solutionwas crash cooled to about 2-8° C. and remained at about 2-8° C. forabout 4 days producing a golden yellow solution with white oil. Thesample was placed at room temperature and after about 14 days, solidswere observed in solution.

A suitable single crystal was selected and analyzed by single-crystalX-ray diffractometry. A colorless plate having approximate dimensions of0.19×0.13×0.06 mm³, was mounted on a nylon loop in random orientation.Preliminary examination and data collection were performed on a RigakuSuperNova diffractometer, equipped with a copper anode microfocus sealedX-ray tube (Cu Kα λ=1.54184 Å) and a Dectris Pilatus3 R 200K hybridpixel array detector. Cell constants and an orientation matrix for datacollection were obtained from least-squares refinement using the settingangles of 15725 reflections in the range 3.5010°<θ<77.2150°. The spacegroup was determined by the program CRYSALISPRO to be C2221(international tables no. 20). The data were collected to a maximumdiffraction angle (20) of 155.284° at room temperature.

It was found that the crystal system of Form I is orthorhombic and thespace group is C2221. The cell parameters and calculated volume are:a=14.77743(18) Å, b=14.62619(16) Å, c=51.7778(8) Å, α=90°, β=90°, γ=90°,V=11191.1(3) Å3. The molecular weight is 569.62 g mol⁻¹ with Z=16,resulting in a calculated density of 1.352 g cm⁻³. Standard uncertaintyfor this data is written in crystallographic parenthesis notation, e.g.0.123(4) is equivalent to 0.123±0.004. The quality of the structureobtained is high, as indicated by the fit residual, R, of 0.0446(4.46%). R-factors in the range 2-6% are quoted to be the most reliablydetermined structures.

It is contemplated that Form I is the most stable form of Compound 1.

Example 3 Production of Form II of Compound 1

100 milligrams of amorphous Compound 1, prepared according to the methodof Example 1, was slurried in dimethylformamide (DMF) and subjected totemperature cycling from 40° C. to 25° C., in 4 h cycles for 72 h. SolidForm II of Compound 1 was collected by filtration. The DSC curve showsthe first endotherm around 74° C. and a second endotherm was observedabove 180° C. (FIG. 37).

Example 4 Production of Form III of Compound 1

100 milligrams of amorphous Compound 1, prepared according to the methodof Example 1, was slurried in dimethylsulfoxide (DMSO) and subjected totemperature cycling from 40° C. to 25° C., in 4 h cycles for 72 h. SolidForm III of Compound 1 was collected by filtration. Thermogravimetricanalysis of Form III showed a large steady weight loss, suggesting thatForm III may be a DMSO solvate of Compound 1. No additional thermalevents were observed above the solvent loss (FIG. 38).

Example 5 Production of Form IV of Compound 1

500 milligrams of amorphous Compound 1, prepared according to the methodof Example 1, was slurried in methanol and subjected to temperaturecycling from 40° C. to 25° C., in 4 h cycles for 48 hours. Solid Form IVof Compound 1 was collected by filtration. DSC curve of Form IVcomprises an endothermic transition with onset at 85° C., about 190° C.,and about 202° C. and exotherm at 146° C.

Thermogravimetric analysis indicated a weight loss of 4.2% or 4.7% andcorresponding endotherm between 82-92° C., indicating that Form IV is amethanol solvate of Compound 1. Upon further heating the sample to 120°C., XRPD analysis confirmed that the sample had converted to Form I.

Example 6 Production of Form V of Compound 1

100 milligrams of amorphous Compound 1, prepared according to the methodof Example 1, was slurried in N-methyl-2-pyrrolidone (NMP) and subjectedto temperature cycling from 40° C. to 25° C., in 4 h cycles for 72 h.Solid Form V of Compound 1 was collected by filtration.Thermogravimetric analysis of Form V showed a large steady weight lossof 13.5%, suggesting that Form V may be a NMP solvate of Compound 1. Noadditional thermal events were observed above the solvent loss (FIG.39).

Example 7 Production of Form VI of Compound 1

100 milligrams of amorphous Compound 1, prepared according to the methodof Example 1, was dissolved in toluene and either crash cooled at −18°C. or the toluene was evaporated. In both cases, solid Form VI ofCompound 1 was collected by filtration. XRPD analysis indicated adistinct toluene solvate form of Compound 1.

Example 8 Production of Form VII of Compound 1

100 milligrams of Form IV of Compound 1, prepared according to themethod of Example 5, was heated to 80° C. in an oven. Form VII wasconfirmed to be a desolvated form of Form IV, produced by drying themethanol solvate Form IV. XRPD analysis showed that while Form VII had asimilar diffraction pattern to that of Form I, there were a number ofdistinct peaks between the two forms which confirmed them to be distinctcrystal forms. Differential scanning calorimetry (DSC) results (FIG. 40)were consistent with thermogravimetric analysis. Onset of the firstendothermic event was observed at 133.7° C. (peak at 141.4° C.), withthe peak of the exotherm at 151.6° C. The main, sharp endotherm wasobserved with an onset at 192.3° C. (peak at 195.0° C.). A smallerendotherm with a peak at 207.0° C. was likely to indicate formation of ahigher melting crystalline form. Dynamic vapor sorption (DVS) analysisof Form VII indicated the material was moderately hygroscopic (>4% wateruptake at 90% RH), and post DVS analysis showed no change in form. Theuptake between 40 and 70% RH could potentially be indicative of hydrateformation (tentatively assigned the name Form IX). Karl-Fischer analysisshowed a water content of 0.503%, consistent with observations ofambient humidity measured during DVS analysis. NMR and IR data confirmedthe structural integrity of Compound 1 present. Aqueous solubility ofForm VII was determined to be 0.109 mg/mL. XRPD analysis confirmed thatprolonged exposure to water resulted in the conversion of Form VII toForm I. However, Form VII was determined to be chemically and physicallystable following 7 days of storage at 40° C. and 75% RH. No change inform was observed, and the purity was determined to be 99.85%.

Example 9 Production of Form VIII of Compound 1

100 milligrams of anhydrous Form VII of Compound 1 was heated to 195° C.Consistent with the DSC analysis of Form VII, XRPD analysis of theresulting solid showed that Form VIII of Compound 1 was produced. TheNMR spectrum was found to be consistent with that of Compound 1, andHPLC analysis of Form VIII indicated a purity of 99.4%. Form VIII wasalso prepared by running 50 grams of anhydrous Form I of Compound 1through a Leistriz twin screw extruder utilizing multiple heat zones ofabout 170 to about 193° C. and a screw speed of 30 rpms.

DSC analysis of Form VIII showed the same sharp peak with onset at204.7° C. (peak at 208.1° C.), corresponding to the melting point ofForm VIII. Further DSC analysis of Form I indicate that cooling a meltedsample of Form I, followed by a second heating event resulted in anendotherm with onset at 204.7° C. (peak at 208.1° C.), indicating thatForm VIII is directly produced from Form I upon heating in that manner.

The DSC curve shown in FIG. 16 shows that Form VIII comprises anendotherm with onset at about 205° C.

Example 10 Competitive Slurrying of Form I and Form VII

Competitive slurrying of Form I and Form VII in acetone,acetonitrile:water (10%), ethanol, and ethyl acetate, at both ambienttemperature and 60° C., resulted in conversion to Form I, as confirmedby XRPD and DSC.

Example 11 Competitive Slurrying of Form I and Form VIII

Competitive slurrying of Form I and Form VIII in acetone,acetonitrile:water (10%), ethanol, and ethyl acetate, at both ambienttemperature and 60° C., resulted in conversion to Form I, as confirmedby XRPD and DSC.

Example 12 Competitive Slurrying of Form I and Form VIII

Competitive slurrying of Form I and Form VIII in a 1:1 ratio in asolution of 6:4 ethanol:water at room temperature for about two weeksresulted in conversion to Form I as confirmed by XRPD.

The results of the competitive slurrying analysis indicated that Form Iis the more thermodynamically stable form between 22-60° C. Form VIIIcould be potentially the more stable form at high temperatures.

Example 13 Production of Compound 1 Sodium Form I

Sodium Form I (hydrate) was prepared as follows. 3.48 g of anhydrousForm I of Compound 1 was placed in a beaker with 0.27 g of NaOH and 40mL of water. The sample was heated and stirred until solution becameclear. Next, the solution was filtered into a vial and placed in avacuum centrifuge. The resulting solids were slurried in ethyl acetateand then washed with acetone, filtered, and dried. The XRPD pattern ofCompound 1 Sodium Form I is shown in FIG. 19. The DSC curve is shown inFIG. 20 and indicates multiple endothermic transitions with onset at 37°C. and 283° C. The TGA curve is shown in FIG. 21 and displays a weightloss (4.1% RT to 175° C.) that was identified as water based on TGA-MassSpectrometry (TGA-MS). Weight loss above 250° C. is attributed todecomposition. The dynamic vapor sorption curve indicates that the formabsorbs about 32 weight % of water up to 95% RH (relative humidity) at25° C. The material was found to have deliquesced post experiment.

Example 14 Production of Compound 1 Sodium Form II

Compound 1 Sodium Form II (variable hydrate) was prepared as follows.4.0 g of anhydrous Form I of Compound 1 was placed in a beaker with 0.4g of NaOH and about 40 mL of water. The sample was heated and stirreduntil solution became clear. Next, the solution was filtered into a vialand placed in a vacuum centrifuge. The resulting solids from vacuumcentrifuge were washed with 10% water in acetonitrile, and then thesolids were dried and then slurried in ethyl acetate. The sample weresonicated for about 1 hour and then left to sit at room temperature. Thesolids were slurried in acetone and a portion was filtered to yieldsolids. The XRPD pattern of Compound 1 Sodium Form II is shown in FIG.22. The DSC curve is shown in FIG. 23 and indicates multiple endothermictransitions with onset at about 19, about 78 and about 136° C. The TGAcurve is shown in FIG. 24 and displays a weight loss (about 24% RT toabout 150° C.) indicating a solvate that was identified as water basedon TGA-MS. A second sample of Compound 1 Sodium Form II was preparedwhen 1092 mg of Form I of Compound 1 was placed in a vial with 76 mg ofNaOH and 10 mL of water. Sample sonicated but solids till persisted.Another 45 mg of NaOH as added with an additional 10 mL and the solutionbecame clear. Sample was then centrifuge evaporated over the weekend toyield dry solids. These solids were then slurried in EtOAc forapproximately 10 days. The resulting solids had the same XRPD pattern asCompound 1 Sodium Form II and was found to only have about 10.4% weightloss up to about 175° C. This may indicate that this form can haveanywhere from about 4-10 moles of water. Weight loss above about 250° C.is attributed to decomposition. The dynamic vapor sorption curveindicates that the form absorbs about 35 weight % of water up to about95% RH at about 25° C. The material was found to have deliquesced postexperiment.

Example 15 Production of Compound 1 Calcium Form I

Compound 1 Calcium Form I (hydrate) was prepared as follows. 4.47 g ofanhydrous Form I of Compound 1 was placed in a beaker with 0.4 g of KOHand about 25 mL of water. The sample was heated and stirred untilsolution became clear. Next, 0.5 g of calcium chloride was added and thesample was cooled to room temperature and left to stir for a few hours.The sample was then filtered and slurried in about 20% water inacetonitrile to yield a hazy solution. The sample was sonicated forabout one hour to yield a slurry. The sample was then filtered and driedin a nitrogen box at 5 psi. The XRPD pattern of Compound 1 Calcium FormI is shown in FIG. 25. The DSC curve is shown in FIG. 26 and indicatesmultiple endothermic transitions with onset at about 17, about 72, about180 and about 202° C. The TGA curve is shown in FIG. 27 and displays aweight loss (about 6.0% RT to about 200° C.) that was identified aswater based on TGA-MS. Weight loss above about 250° C. is attributed todecomposition. The dynamic vapor sorption curve indicates that the formabsorbs about 9 weight % of water up to about 95% RH at about 25° C.XRPD analysis of the sample after the DVS experiment shows that thematerial had not changed form.

Example 16 Production of Compound 1 Magnesium Form I

Compound 1 Magnesium Form I (hydrate) was prepared as follows. 987.6milligrams of anhydrous Form I of Compound 1 was placed in a vial with156 milligrams of KOH and about 10 mL of water. The sample was sonicatedand heated until the solution became clear. Next, 130 milligrams ofmagnesium acetate tetrahydrate was added, and the sample was left tostir at room temperature for about 3 days then isolated. The XRPDpattern of Compound 1 Magnesium Form I is shown in FIG. 28. The DSCcurve is shown in FIG. 29 and indicates a single endotherm with onset atabout 53° C. The TGA curve is shown in FIG. 30 and displays a weightloss (about 13.8% RT to about 150° C.) that was identified as waterbased on TGA-MS. Weight loss above about 250° C. is attributed todecomposition. The dynamic vapor sorption curve indicates that the formabsorbs about 8 weight % of water up to about 95% RH at about 25° C.XRPD analysis of the sample after the DVS experiment shows that thematerial had not changed form.

Example 17 Production of Compound 1 Diethanolamine Form I

Compound 1 Diethanolamine Form I (hydrate) was prepared as follows.106.9 milligrams of anhydrous Form I of Compound 1 was dissolved inabout 3 mL of acetone. 20 μL of diethanolamine was added, and the samplewas sonicated for about 2 hours. An additional about 40 μL ofdiethanolamine was then added, and the sample further slurried at roomtemperature and then isolated. The XRPD pattern of Compound 1Diethanolamine Form I is shown in FIG. 31. The DSC curve is shown inFIG. 32 and indicates an endothermic transition with onset at about 118°C. The TGA curve is shown in FIG. 33 and displays a weight loss (about2.7% RT to about 150° C.) that was identified as water based on TGA-MS.Weight loss above about 250° C. is attributed to decomposition. Thedynamic vapor sorption curve indicates that the form absorbs about 14wt. % of water up to about 95% RH at about 25° C. XRPD analysis of thesample after the DVS experiment shows that the material had not changedform.

Example 18 Production of Compound 1 Piperazine Form I

Compound 1 Piperazine Form I (hydrate) was obtained as follows:anhydrous Form I of Compound 1 was placed in a centrifuge tube and onemolar ratio of a piperazine was also added. Next, 30 μl of MeOH wasadded to the powders, and the sample was sonicated for about 30 minutes.The sample tube was then opened and allowed to dry in a nitrogen box.The XRPD pattern of Compound 1 Piperazine Form I is shown in FIG. 34.The DSC curve is shown in FIG. 35 and indicates multiple endothermictransitions with onset at about 27 and about 139° C. The TGA curve isshown in FIG. 36 and displays a weight loss (about 7.3% RT to about 100°C.) that was identified as water based on TGA-MS. Weight loss aboveabout 250° C. is attributed to decomposition. The dynamic vapor sorptioncurve indicates that the form absorbs about 1.5 wt. % of water up toabout 95% RH at about 25° C. XRPD analysis of the sample after the DVSexperiment shows that the material had not changed form.

Example 19 X-ray Powder Diffraction (XRPD) Analytical Method A

XRPD analysis of amorphous and Forms II, III, IV, V, VI, VII, and VIIIof Compound 1 was carried out on a Siemens D5000 diffractometer,scanning the samples between 3 and 30 degrees 2θ. Material was gentlycompressed on a glass disc inserted into a sample holder. The sample wasthen loaded into the diffractometer running in reflection mode, and theanalysis was conducted using the following experimental conditions.

Raw Data Origin Siemens-binary V2 (.RAW) Start Position (°2θ) 3.0000 EndPosition (°2θ) 30.0000 Step Size (°2θ) 0.0200 Scan Step Time (seconds) 1Scan Type Continuous Slit Types Fixed Divergence Slit Size (mm) 2.0000Receiving Slit Size (mm) 2.0000 Detector Slit Size (mm) 0.2000Measurement Temperature (° C.) 20.00 Anode Material Cu K-Alpha1 (Å)1.54060 K-Alpha2 (Å) 1.54443 K-Beta (Å) 1.39225 K-A2/K-A1 Ratio 0.50000(nominal) Generator Settings 40 mA, 40 kV Focussing Circle Diameter (mm)401.00 Diffracted Beam Monochromator Graphite Spinning No

Example 20 X-ray Powder Diffraction (XRPD) Analytical Method B

XRPD analysis of Form I of Compound 1 was carried out on a PANalyticalCubix Pro diffractometer. The sample was placed into the sample holder,such that the sample of Compound 1 was level with the zero height forthe instrument. The following parameters were used to acquire the XRPDpattern of Form I of Compound 1.

Start Position (°2θ) 3.0100 End Position (°2θ) 45.0100 Input Step Size(°2θ) 0.03 Actual Step Size (°2θ) 0.02 Time Per Step (seconds) 10.1600Active Length (°2θ) 2.54 Scan Mode Continuous Voltage (kV) 45 Current(mA) 40 Anode Cu ASS Primary Slit Fixed 1° Divergence Slit (Prog.)Automatic - 5 mm Soller Slits (RS) 0.02 radian Scatter Slit (PASS)Automatic - 5 mm Spinner 2

Example 21 X-ray Powder Diffraction (XRPD) Analytical Method C

X-ray powder diffraction (XRPD) analysis of Compound 1 Sodium Form I,Compound 1 Sodium Form II, Compound 1 Calcium Form I, Compound 1Magnesium Form I, Compound 1 Diethanolamine Form I, or Compound 1Piperazine Form I was conducted on a diffractometer (PANalyticalXPERT-PRO, PANalytical B. V., Almelo, Netherlands) using copperradiation (Cu Kα λ=1.541874). Samples were spread evenly on a zerobackground sample plate. The generator was operated at a voltage of 45kV and amperage of 40 mA. Slits were Soller 0.02 rad, antiscatter 1.00,and divergence. Scans were performed from 2 to 40° 2θ with a 0.0167 stepsize. Data analysis was performed using X′Pert Data Viewer V1.2d(PANalytical B.V., Almelo, Netherlands).

Example 22 Thermogravimetric/Differential Thermal Analysis (TG/DTA)

For each analysis as discussed in Examples 3 to 6 and 8, 5 milligrams ofmaterial was weighed into an open aluminum pan and loaded into asimultaneous TG/DT analyzer and held at room temperature. The sample wasthen heated at a rate of 10° C./min from 25° C. to 300° C. during whichtime the change in sample weight was recorded along with anydifferential thermal events (DTA). Nitrogen was used as the purge gas,at a flow rate of 100 cm³/min.

For Examples 2, 5, 7, 9, and 13 to 18, TGA was used to evaluate sampleweight loss as a function of temperature by loading 1-10 milligrams ofmaterial onto a an aluminum weigh pan (TA Instruments, New Castle, Del.)and heated the sample to 350° C. or above at a rate of 10° C./min. Thesample and reference pans were under a 60 mL/min and 40 mL/min nitrogenpurge, respectively. Data analysis was completed using UniversalAnalysis 2000 Version 4.7A (TA Instruments, New Castle, Del.).

Example 23 Differential Scanning Calorimetry (DSC)

For each analysis as discussed in Examples 8 to 11, 5 milligrams ofmaterial was weighed into an aluminum DSC pan and sealednon-hermetically with a pierced aluminum lid. The sample pan was thenloaded into a Seiko DSC6200 (equipped with a cooler), and cooled to andheld at 25° C. Once a stable heat-flow response was obtained, the sampleand reference were heated to approximately 280° C. (or degradationtemperature observed by TG/DTA) at a scan rate of 10° C./min, and theresulting heat flow response was recorded.

For Examples 2, 5, 7, 9, and 13 to 18, DSC was run by loading 1-5milligrams of material into a crimped Tzero standard aluminum pan andheating the sample at 10° C./min from 20 to 300° C. or above. The sampleand reference pans were under a 50 mL/min nitrogen purge. Data analysiswas completed using Universal Analysis 2000 Version 4.7A (TAInstruments, New Castle, Del.).

Example 24 Karl-Fischer Coulometric Titration (KF)

Prior to analyzing a compound sample, a blank sample containing methanolonly was analyzed using a Mettler Toledo C30 Compact Titrator, todetermine the blank water content. Approximately 10-15 milligrams ofsolid material was accurately weighed into a vial. The material was thendissolved in methanol and the amount added was recorded. The resultantwas then manually introduced into the titration cell of the instrument.The water content was calculated as a percentage and the value recorded.

Example 25. Infrared Spectroscope (IR)

Infrared spectroscopy was carried out on a Bruker ALPHA P spectrometer.Sufficient material was placed onto the center of the plate of thespectrometer and the spectra were obtained using the followingparameters.

Resolution (cm⁻¹)  4 Background Scan Time (scans) 16 Sample Scan Time(scans) 16 Data Collection Range (cm⁻¹) 4000-400 Result SpectrumTransmittance Software OPUS v.6

Example 26 Dynamic Vapor Sorption (DVS)

For DVS analysis as discussed in Example 8, approximately 10 milligramsof sample was placed into a mesh vapor sorption balance pan and loadedinto a DVS-1 dynamic vapor sorption balance (Surface MeasurementSystems). The sample was subjected to a ramping profile from 0-90%relative humidity (RH) at 10% increments, maintaining the sample at eachstep until a stable weight had been achieved (99.5% step completion).After completion of the sorption cycle, the sample was dried using thereverse procedure, lowering the RH to 0%. The weight change during thesorption/desorption cycles was plotted.

For Examples 2, 5, 7, 9, and 13 to 18, hygroscopicity was studied usingdynamic vapor sorption (DVS, TA Q5000 SA, TA Instruments, New Castle,Del. or DVS, DVS Intrinsic, Surface Measurement Systems, London, UK). Asample (2-20 mg) was placed in an aluminum DVS pan and loaded on thesample side of the twin pan balance. The water sorption and desorptionwere studied as a function of relative humidity (RH) at 25° C. In 10% RHincrements, the relative humidity was increased from 5% RH to 95% RH andthen decreased back to 5%. Each relative humidity increment had anequilibration time of 180 minutes, unless weight change % was less than0.002% in 30 minutes. Data analysis was performed using UniversalAnalysis 2000 Version 4.7A (TA Instruments, New Castle, Del.) for TA DVSruns and Microsoft Excel for SMS DVS runs.

Example 27 High Performance Liquid Chromatography-Ultraviolet Detection(HPLC-UV)

Purity and concentration analyses were carried out using the followingmethod:

Instrument Agilent 1100 Column Waters XBridge C18 3.5μ 150 × 3 mm ColumnTemperature (° C.) 40 Autosampler Temperature (° C.) 20 UV Wavelength(nm) 315 Injection Volume (μL) 5 Flow Rate (mL/min) 0.8 Mobile Phase A0.05% TFA in water Mobile Phase B 0.05 TFA in acetonitrile GradientProgram Time (min) Solvent B (%) 0.0 25 25.0 75 30.0 95 35.0 95 35.1 2540.0 25

Example 28 pKa Measurements

pKa analysis was performed using a UV-metric method. The sample wastitrated in a triple titration (pH 12.1 to pH 2) at concentrations of 32to 20 μM under methanol-water co-solvent conditions (the methanolconcentration varied from 53-30% (v/v). The pKa was determined using thespectroscopic data by a Yasuda-Shedlovsky extrapolation of the resultsfrom each titration.

Example 29 LogP and LogD Determination

LogP analysis was performed using a potentiometric (pH-metric) method.The sample was titrated in various ratios of octanol/water in twotitrations covering the pH range from 1.9 to 12.0 at concentrations of1.0 to 0.6 mM. The shift of the aqueous pKa in the presence of octanolwas used to determine logP of the neutral and anionic species. From thisinformation a lipophilicity profile was constructed, such that that logDat a given pH could be determined.

Example 30. Pharmaceutical Composition

A pharmaceutical composition comprising Form I of Compound 1 wasprepared that contains the following ingredients.

Capsule Strength Ingredient Quality Standard 10 mg 50 mg 200 mg Compound1 (Form I) In-house  17.00 g 110.0 g 640.0 g Gelucire ® 50/13 (stearoylmacrogol- USP/NF, Ph. Eur. 153.00 g 198.0 g 288.0 g 32 glycerides;surfactant) Fast Flo ® 316 (lactose monohydrate; NF 556.75 g 632.5 g440.0 g filler) Ac-Di-Sol ® SD-711 (croscarmellose NF, Ph. Eur., JP 38.25 g  49.5 g  72.0 g sodium, disintegrant) Theoretical Batch Size(g) 765.00 g 990.0 g 1440.0 g  Theoretical Batch Size (# capsules) 17002200 3200

The pharmaceutical composition was prepared as follows.

Example 31 Micronization

Crystalline Compound 1 (Form I) was continuously fed into a 2 inchvertical loop jet mill. The compressed air supply was high puritynitrogen, with an inlet pressure of at least 110 p.s.i. The pushernozzle and grinder nozzle pressures were both maintained at 80 p.s.i.throughout the milling process. The feed rate was controlled by avibratory feeder, at an equipment set point of 3. Approximately 800grams of material was generated over the course of approximately 5 hoursin this manner. This material was then collected in a single containerand mixed prior to incorporation into the hot melt granulations at 10milligrams, 50 milligrams, and 200 milligrams dosage strengths.

Example 32 Hot Melt High Shear Granulation, Milling, and Blending

The granulations were prepared in a jacketed 4 L bowl on a Vector GMXLab-Micro High Shear granulator. The bowl was jacketed with water at 60°C. Approximately half of the lactose monohydrate, croscarmellose sodium,and the micronized Compound 1 drug substance were added to the bowl. Theremaining lactose was then used to dry wash the Compound 1 drugsubstance transfer container prior to addition to the bowl. The dry,solid components were then mixed until the blend reaches 55° C. Oncethis temperature is reached, the Gelucire 50/13 melted, and thegranulation continued mixing until the product temperature drop occurredas the Gelucire 50/13 melts. The granulation continued mixing until theproduct temperature recovered to 55° C. to ensure complete melting andmixing of the Gelucire 50/13. This granulated product was then allowedto cool to room temperature. The cooled granulation was milled using aQuadro Comil 197S equipped with a 1905 m screen and a round impeller.

Example 33 Capsule Preparation

The powder prepared in Example 22 was encapsulated using a Profillapparatus into size 0 white opaque gelating capsules, which were thendedusted. The final capsule drug product had a fill weight of 450 mg, ofwhich 90 milligrams was Gelucire 50/13, 22.5 milligrams wascroscarmellose sodium, and the remaining weight was comprised of lactosemonohydrate and micronized Compound 1 drug substance. The amount of eachof lactose monohydrate and Compound 1 was dependent on the dosagestrength, with their combined weight equal to 337.5 to achieve a total450 milligrams fill weight. A 100% weight sort was carried out, and thefinal product was packaged in white opaque HDPE bottles, which were theninduction sealed.

Example 34 Synthesis of Intermediate (R)-G-1-a

Step 1. Synthesis of rac-G-7-a

A 1000 L reactor was charged with 330 kg DMSO, and potassium t-butoxide(30 kg, 1.22 eq) were added at 10-25° C. Trimethylsulfoxonium iodide (58kg, 1.2 eq) was added in several portions at 18-25° C., and the mixturewas stirred in that temperature range for two hours.2-Methoxybenzaldehyde (30.15 kg, 1.0 eq) was added in several portionswhile maintaining the reactor temperature between 18-25° C. The mixturewas stirred at a temperature between 18-25° C. until2-methoxybenzaldehyde was determined to be present at less than 0.5% byHPLC (typically 1-2 hours), whereupon 300 kg water was added to quenchthe reaction, maintaining the temperature below 25° C. The reactionmixture was extracted with heptane (3 portions of 204 kg), and theheptane extracts were combined, washed with water (3 portions of 300kg), then brine (300 kg). The organic layer was concentrated undervacuum at 40-45° C., affording rac-G-7-a (18.55 kg, 56% isolated yield,HPLC purity 96.6% at 220 nm, 94% wt. by NMR) as an oil, which was usedin the next step without any further purification.

Alternative Step 1: Synthesis of rac-G-7-a

To 2-methoxybenzaldehyde (1 eq) was added trimethylsulfonium methylsulfate (1.08 eq), followed by dichloromethane (about 75.5 mL), and theresulting mixture was agitated. To the mixture was added ca. 50 wt %aqueous NaOH portion wise and stirred for about 2.5 hours at atemperature range of about 28° C. to about 22° C. Additional water wasadded, and the mixture cooled to a temperature of about 17° C.Dichloromethane was added to the mixture and stirred. The mixture wasseparated, and the organic layer was concentrated under vacuum, toprovide rac-G-7-a. ¹H NMR (400 MHz, CDCl₃): δ 7.28-7.25 (m, 1H), 7.15(d, J=7.5 Hz, 1H), 6.94 (t, J=7.5 Hz, 1H), 6.88 (d, J=8.2 Hz, 1H), 4.21(t, J=2.9 Hz, 1H), 3.87 (s, 3H), 3.14 (t, J=4.9 Hz, 1H), 2.71 (dd,J=5.6, 2.4 Hz, 1H).

Step 2. Synthesis of rac-G-5-a

Tetrahydro-2H-pyran-4-ol (16.3 kg, 4.0 eq) was charged into a 50 Lreactor, followed by FeCl₃ (225 g, 0.035 eq). Intermediate rac-G-7-a(6.0 kg, 1.0 eq) was added dropwise, maintaining the temperature between−10 to 10° C. The reaction was stirred at between 0-10° C. until thestarting epoxide was shown to be present at less than 0.5% by HPLC(typically 0.5-1 hours). Once the reaction was judged to be complete,the reaction mixture was diluted with toluene (240 L), and the toluenesolution was extracted with water (3 portions of 24 kg), then brine (12kg). The organic layer was concentrated under vacuum between 40-45° C.,affording rac-G-5-a (19.64 kg, 47% yield) as an oil.

Alternative Step 2: Synthesis of rac-G-5-a

Toluene is charged to a reactor, followed by tetrahydro-2H-pyran-4-ol (4eq), BF₃-Et₂O (0.005 v/w). Intermediate rac-G-7-a (1.0 eq) is addeddropwise, maintaining the temperature between 0 to 10° C. The reactionis stirred for about an hour at a temperature between 0 to 10° C. Thesolution is combined with toluene (about 8 v/w) at about 15 to 25° C.and washed with water about three times. The water layers are combined,washed with MTBE, and the MTBE layers are washed with water about twotimes. The organic layers are then combined and concentrated undervacuum. To the resulting residue, THF is added, and the mixture isconcentrated under vacuum, affording rac-G-5-a as an stock solution.

Step 3. Synthesis of (R)-G-5-a

A 50 L glass reactor was charged with toluene (5.0 v/w), followed byrac-G-5-a (6.2 kg, 1.0 eq) in one portion. The solution was warmed to40° C. until the mixture became a clear solution, then cooled to 25° C.Vinyl butyrate (0.5 eq) was added in one portion to the above solution,and the mixture was stirred for 0.5 hours at a temperature between25-30° C. until a clear solution was obtained. CAL-B lipase (1.5% w/w)was added in one portion to the reactor and the mixture was stirred at22-26° C. until the reaction was deemed complete when IPC showed theratio of (S)-G-5-a/(R)-G-5-a was 96:3.5 and the e.e. of (R)-G-8-a was97.9% (typically 4 hours). The CAL-B was filtered out, and the filtercake washed with THF (11.6 L). The filtrate was combined with that ofanother batch of the same scale, and the combined filtrates wereconcentrated under vacuum at 35-40° C. until 13 L of residue remained.Petroleum ether (5.0 v/w) was added, and the mixture stirred for 30minutes. The precipitated (S)-G-5-a was filtered, and the filter cakewashed with petroleum ether (2.0 v/w). The filtrate was concentratedunder vacuum at a temperature between 40-45° C., resulting in a crudeoil. Toluene (3.0 v/w) was added to a 50 L glass reactor, followed bythe oil from the previous step. Succinic anhydride (0.25 eq.) anddimethylaminopyridine (DMAP, 0.02 eq.) were added, and the mixture washeated to between 70-80° C. and stirred for two hours, samplingperiodically until the amount of (S)-G-5-a remaining was no more than0.5% by HPLC. The mixture was then cooled to between 10-20° C. andwashed with saturated aqueous sodium bicarbonate (two portions of 1.0v/w). HPLC analysis of the organic layer showed that the amount of(S)-G-5-a present was less than 0.1%. The organic solvent wasconcentrated to give an oil (9.9 kg, 53.6% yield, 89% purity, 97% e.e.)which was used in the next step without further purification. To a 100 Lreactor was added methanol (40 L), followed by the oil from the previousstep, followed by water (30 kg, 3.0 w/w). Sodium hydroxide (1.23 kg) inseveral portions while maintaining the temperature between 10-25° C. Thereaction was stirred at that temperature until HPLC analysis indicatedthat the butyrate ester was completely consumed. The pH was adjusted to7 with 3 N aqueous HCl, and the mixture was concentrated at vacuumbetween 40-45° C. until 30 volumes remained. The mixture was filteredand the filter cake was collected to give crude (R)-G-5-a (9.0 kg, 96%purity, 96.8% e.e.). Ethyl acetate (4.3 L) and petroleum ether (26 L)were charged into a reactor, followed by the crude product from theprevious step. The mixture was stirred for 1 hour at a temperaturebetween 10-25° C., then filtered. The collected solids were dried in avacuum oven at between 40-45° C., yielding pure (R)-G-5-a (5.2 kg, 70%yield for this step, 99% purity, 96% e.e.) as an off-white solid.

Alternate Step 3: Alternate Synthesis of (R)-G-5-a

A 50 L glass reactor was charged with THF (29 L), followed by rac-G-5-a(5.8 kg, 1.0 eq) in one portion. Succinic anhydride (2.3 kg, 1.0 eq) wasadded in one portion to the above solution, and the mixture was stirredfor 0.5 hours at a temperature between 25-30° C. until a clear solutionwas obtained. CAL-B lipase (406 g, 7% w/w) was added in one portion tothe reactor and the mixture was stirred at 25-30° C. until the reactionwas deemed complete (when the ratio of G-5-a to (R)-G-8-b was shown tobe 51:49 by IPC (typically 24 hours). The CAL-B was filtered out, andthe filter cake washed with THF (11.6 L). The filtrates were combinedand concentrated under vacuum at 35-40° C. The resulting residue wasdiluted with ethyl acetate (58 L) at 15-25° C., and the ethyl acetatewas washed with saturated sodium bicarbonate (four portions of 23 L) at15-25° C. A sample from the ethyl acetate layer was analyzed by HPLC,which indicated that the ratio of (R)-G-8-b to G-5-a was no more than1:99. The aqueous layers were combined and washed with ethyl acetate(three portions of 29 L). A sample from the aqueous layer was analyzedby HPLC, which indicated that the ratio of (R)-G-8-b to G-5-a wasgreater than 99.5:0.5. To the aqueous layer was added sodium hydroxide(5.8 kg) in several portions at a temperature between 15-25° C. Thereaction was stirred at that temperature for 0.5-1 hours, until HPLCanalysis indicated that the ratio of (R)-G-8-b to (R)-G-5-a was nogreater than 1:99. The reaction mixture was filtered, and the filtercake was washed with water (5.8 L). The filter cake was dried at 40-45°C. to constant weight, yielding 2.4 kg of crude (R)-G-5-a with 96%purity and 98.9% e.e. Crude material from multiple batches was purifiedby recrystallization as follows. Into a 100 L reactor containing ethylacetate (72 L, 6 volumes), was charged crude (R)-G-5-a (12 kg), and themixture was warmed to 30-35° C. and stirred for 1 hour. The solution wasfiltered to remove undissolved solids, and the filtrate was concentratedunder vacuum at 40-45° C. until approximately two volumes of solventremained. To this solution was added heptanes (120 L, 10 volumes), andthe mixture was heated to reflux to obtain a clear solution. Thesolution was cooled to a temperature between 15-20° C. gradually overeight hours, and stirred for 12 hours at that temperature. The resultingsolids were collected by filtration, and the filter cake was washed witha solution of ethyl acetate/heptanes (1:5, 12 L) once. The cake wascollected and dried at 40-45° C. to constant weight, providing 10.2 kgof (R)-G-5-a (99.2% purity by HPLC, 99.8% e.e.) as an off-white solid.

Synthesis of (R)-G-5-a was also carried out similar to the methoddescribed above with Novozyme 435 in place of CAL-B lipase.

Step 4. Synthesis of (R)-G-6-a

Into a 100 L glass reactor under nitrogen, was charged dichloromethane(58 L) followed by (R)-G-5-a (5794 g, 1.0 eq.), and triethylamine (4.8L), and the reaction mixture was cooled to between 0-10° C.Methanesulfonyl chloride (3160 g) was charged over 35 minutes,maintaining the reaction temperature no higher than 25° C. Then themixture was stirred at between 20-30° C. for 18 hours, whereupon theamount of (R)-G-5-a remaining was determined to be no more than 1%.Purified water (58 L) was added, and the mixture was transferred to a200 L glass reactor and stirred for at least one hour. The phases wereseparated and the organic layer was transferred to a 100 L reactor andwashed with 2 N HCl (29 L), then 10% aqueous sodium bicarbonate (29 L),and the organic layer was concentrated under vacuum at 70° C. to avolume of 29 L. Isopropanol (58 L) was added and the mixture wasconcentrated under vacuum at 70° C. to a volume of 29 L. Isopropanol (58L) was again added, and the mixture was concentrated to a final volumeof 28 L. Purified water (29 L) was added, and the mixture was heated tobetween 50-60° C. with stirring until complete dissolution was observed.The mixture was then cooled to between 0-10° C. and stirred for at least14 hours. The resulting solids were collected by filtration, washed withpurified water (12 L), and dried in a vacuum oven at 25° C. for at least12 hours. The isolated intermediate (R)-G-6-a (6962 g) was used withoutfurther purification in the next step.

Alternative Step 4. Synthesis of (R)-G-6-a

2-Methyltetrahydrofuran (1300 mL) was charged to a reactor containing(R)-G-5-a (200 g, 1.0 equiv.), followed by trimethylamine (120 g, 1.5equiv.). The contents were cooled to 5° C. (2 to 8° C.) andmethanesulfonyl chloride (109 g, 1.2 equivalents) was charged whilemaintaining the reaction contents at no more than about 25° C.2-Methyltetrahydrofuran (120 mL) was used to rinse forward themethanesulfonyl chloride and the reaction was warmed to about 22° C. andstirred until the reaction was complete. Water (1600 mL) was then slowlyadded such that the internal temperature was less than about 40° C. andthe solution was agitated for about 30 minutes. Agitation was stoppedand the solution was allowed to settle. The bottom aqueous layer wasremoved and the organic layer was washed with an aqueous HCl solution(about 160 g concentrated HCl in 664 g water) at about 22° C. Agitationwas again stopped and the solution was allowed to settle. The bottomaqueous layer was removed and the organic layer was then washed with anaqueous sodium bicarbonate solution (about 72 g NaHCO₃ in 776 g water)at about 22° C. Agitation was again stopped and the solution was allowedto settle. The bottom aqueous layer was removed and the organic layerwas then washed with water (800 mL, about 4.0 v/w (R)-G-5-a). Agitationwas again stopped and the solution was allowed to settle. The bottomaqueous layer was removed. The organic layers were distilled undervacuum to about 3V pot volume. 2-Propanol (1200 mL, about 6.0 v/w(R)-G-5-a) was added and the reaction was distilled to about 6V potvolume twice. Water (1000 mL, about 5.0 v/w (R)-G-5-a) was then addedand the solution warmed to between about 55° C. to about 65° C. Thesolution was then cooled to about 22° C. (19 to 25° C.) and (R)-G-6-aseeds (made according to this method or from a previous alternate routesuch as described herein) (0.6 g, about 0.003 w/w (R)-G-6-a) were addedand the solution was cooled to about 5° C. and filtered. The filter cakewas washed with water (about 400 mL, 2.0 v/w (R)-G-6-a) and dried toafford (R)-G-6-a. ¹H NMR (400 MHz, CDCl₃): δ 7.48 (d, J=7.6 Hz, 1H),7.33 (t, J=8.0 Hz, 1H), 7.02 (t, J=7.6 Hz, 1H), 6.91 (d, J=8.0 Hz, 1H),5.21 (d, J=8.0 Hz, 1H), 4.34 (d, J=10.8 Hz, 1H), 4.19 (dd, J=8.0, 10.8Hz), 4.01 (m, 1H), 3.90 (m, 1H), 3.87 (s, 3H), 3.55 (m, 1H), 3.40 (dq,J=9.8, 2.2 Hz, 2H), 3.04 (s, 3H), 2.02 (m, 1H), 1.82 (m, 1H), 1.66 (m,2H).

Step 5. Synthesis of (R)-G-1-a

Into a 100 L reactor under nitrogen was charged N-methylpyrrolidinone(NMP, 14 L), and the reactor was cooled to 0-10° C. Lithium bromide(9189 g) was added in three portions over one hour to the reactorallowing the temperature to return to between 0-10° C. after eachaddition. The mixture was heated to between 55-65° C. (R)-G-6-a (6962 g)was combined with in NMP (14 L) in a 72 L reactor and stirred at 30-40°C. until completely dissolved. This solution was transferred to the 100L reactor containing the lithium bromide solution, and the mixture wasstirred at 50-60° C. for 18 hours, taking samples for analysis by HPLCevery hour, until the amount of (R)-G-6-a remaining was no more than 1%.The contents of the 100 L reactor were cooled to 15-25° C. andtransferred to a 200 L glass reactor together with purified water (70 L)and ethyl acetate (70 L), and the mixture was stirred for at least 15minutes, then the phases were separated. The aqueous phase was extractedwith ethyl acetate (35 L) with stirring for at least 15 minutes. Thecombined organic phases were washed with two portions of brine (35 Leach) and two portions of purified water (35 L each), then concentratedto dryness under vacuum at 40-50° C., affording (R)-G-1-a (6691 g, 92%yield) as an oil.

Alternative Synthesis of (R)-G-1-a

1-Methyl-2-pyrolidinone (NMP) (148 g, about 2.4 v/w was charged to areactor, agitated, and adjusted to about 5° C. Lithium bromide (26.4 g,about 0.44 w/w (R)-G-6-a, 1.67 equiv.) was then added batch-wise to thereactor and agitated for about 30 minutes. Once the temperature reachedabout 5° C., the next charge of lithium bromide (26.4 g, about 0.44 w/w(R)-G-6-a, 1.67 equiv.) was performed. Once the reaction cooled backdown to about 5° C., a third and final charge of lithium bromide (26.4g, about 0.44 w/w (R)-G-6-a, 1.67 equiv.) was performed. Additional NMP(37.1 g, about 0.6 v/w (R)-G-6-a) was added and the temperature wasadjusted to about 55° C. In a separate reactor was charged (R)-G-6-a(60.0 g, about 1.0 equivalent) followed by NMP (80.3 g, about 2.3 v/w(R)-G-6-a), which was then heated to about 30° C. to about 38° C. withagitation until all solids were dissolved. The NMP solution of (R)-G-6-awas charged to the about 55° C. NMP lithium bromide slurry. The(R)-G-6-a solution was rinsed forward with NMP (43.3 g, about 0.7 v/w(R)-G-6-a) and then stirred at about 55° C. Once complete, the pottemperature was adjusted to about 22° C., and water (300.1 g, about 5v/w (R)-G-6-a) was charged slowly to quench the reaction such that thepot temperature remains no more than about 30° C. Ethyl acetate (271.0g, about 5 v/w (R)-G-6-a) was charged and the solution was agitated. Thelayers were allowed to separate and the aqueous layer was removed andset aside. To this aqueous layer was charged ethyl acetate (271.1 g,about 5 v/w (R)-G-6-a) and the solution was agitated. The layers werethen allowed to separate, and the aqueous layer was disposed of. Theethyl acetate organic layers were combined and brine was added [(water,291.0 g, 4 about. 85 v/w (R)-G-6-a), (sodium chloride, 29.1 g, about0.485 w/w (R)-G-6-a)], the temperature was adjusted to about 22° C., andthe mixture agitated. The layers were then separated. The organic layerwas washed with water (300.0 g, about 5 v/w (R)-G-6-a) and the mixtureagitated. The water layer was discarded, and another final water (300.0g, about 5 v/w (R)-G-6-a) wash was performed. The organic layer wasdistilled to about 3V (pot volume) with max jacket temperature at about45° C. Once at about 3V, acetonitrile (ACN) (376.0 g, about 8 v/w(R)-G-6-a) was charged to the reactor and contents distilled down toabout 3 V (pot volume) with max jacket temperature at about 45° C. NMP(185.0 g, about 5.5 v/w (R)-G-6-a) was then added, and the contentsdistilled to about 3.3 V (pot volume) with max jacket temperature atabout 90° C. Once distillation was complete, a NMP stock solution of(R)-G-1-a was achieved.

Example 35 Synthesis of Compound 1—Route A

Step 1. Synthesis of Ethyl4-methyl-2-[3-(1-methyl-1-tert-butoxycarbonylethyl)ureido]-3-thenoate

Into a 300 L reactor under nitrogen was added dichloromethane (136.47L), followed by ethyl 2-amino-4-methylthiophene-3-carboxylate (12.91 kg,1.0 eq) at 15-25° C. Carbonyldiimidazole (12.66 kg, 1.1 eq) was added,while maintaining the temperature between 15-25° C. The mixture wasstirred at that temperature, taking samples and quenching with methanoland analyzing by IPC until the starting material was determined to bepresent at 2.0% or less (typically 12 hours). Once this criterion wasmet, trimethylamine (7.80 kg, 1.1 eq) was added dropwise at atemperature below 25° C. tert-Butyl 2-amino-2-methylpropionatehydrochloride (14.98 kg, 1.1 eq) was added in portions, maintaining thetemperature below 25° C. The reaction was stirred for 5 hours at atemperature between 15-25° C., taking samples, quenching with methanoland analyzing with IPC until the intermediate isocyanate was determinedto be present at 3.0% or less. Once this criterion was met, purifiedwater (52.52 L) was charged into the reactor, and the mixture wasstirred for 30 minutes, then allowed to stand for 15 minutes. The phaseswere allowed to separate and the organic layer was collected and washedwith water (two portions of 52.50 L). The organic layer was concentratedunder vacuum at a temperature below 40° C. until no more than fourvolumes of solvent remained. MTBE (39.27 L, 3 volumes) was charged intothe reactor, and the mixture was again concentrated under vacuum at atemperature below 40° C. until no more than four volumes of solventremained. Again, MTBE (39.27 L, 3 volumes) was charged into the reactor,and the mixture was again concentrated under vacuum at a temperaturebelow 40° C. until no more than four volumes of solvent remained.Petroleum ether (40.00 L, 3 volumes) was charged into the reactor, andthe mixture was stirred for five hours between 15-25° C. The mixture wascentrifuged, filtered, and the resulting cake was washed with petroleumether (13.11 L, 1 volume), then dried in a vacuum oven at 35-45° C. forsix hours, resulting in 23.38 kg of the desired product (90.5% yield,98.0% yield) as an off-white solid.

In some embodiments, heptanes is used in place of petroleum ether.

Step 2. Synthesis of Ethyl5-bromo-4-methyl-2-[3-(1-methyl-1-tert-butoxycarbonylethyl)ureido]-3-thenoate

Into a 500 L reactor under nitrogen was charged DMF (279.47 L) followedby ethyl4-methyl-2-[3-(1-methyl-1-tert-butoxycarbonylethyl)ureido]-3-thenoate(23.38 kg, 1.0 eq.). The mixture was cooled to −10 to 0° C., andN-bromosuccinimide (11.22 kg, 1.0 eq.) was added batchwise, maintainingthe temperature below 0° C. The mixture was stirred at that temperaturefor one hour, sampling and assaying by IPC each half an hour until nomore than 2.0% of the starting material remained. Once the reaction wasdeemed complete according to this criterion, the mixture was poured intopurified water (1000 L, 42 volumes) slowly, and stirred for two hours.The mixture was centrifuged, filtered, and the collected solids werewashed with water (48.00 L, 2 volumes), then dried for 12 hours at35-45° C. in a vacuum oven. The product (26.20 kg, 92.39% yield, 98.8%purity) was isolated as an off-white solid, and had a water content lessthan 0.07% by Karl Fischer titration.

In some embodiments, about 15 volumes of purified water can be used inplace of 42 volumes.

Step 3. Synthesis of tert-Butyl2-(2-bromo-3-methyl-4,6-dioxo-1-thia-5,7-diaza-5,7-dihydroinden-5-yl)-2-methylpropionate(G-2-a)

Into a 1000 L reactor under nitrogen was charged 1,4-dioxane (393 L, 30volumes, 0.03% water by Karl Fischer), followed by ethyl5-bromo-4-methyl-2-[3-(1-methyl-1-tert-butoxycarbonylethyl)ureido]-3-thenoate(13.09 kg, 1.0 eq.). Potassium tert-butoxide (16.27 kg, 5.0 eq.) wasadded in batches. The mixture was heated to between 40-50° C., andstirred at that temperature for approximately 1 hour, sampling andassaying by HPLC every 30 minutes until the content of the startingmaterial was determined to be no more than 2.0%. Once the reaction wasdetermined to be complete, the mixture was cooled to between 20-30° C.,and then poured into a solution of ammonium chloride (327.50 kg) inwater (1310.00 kg, 100 volumes) that had been cooled to between 0-10° C.The quenched mixture was stirred for two hours at a temperature between0-10° C., whereupon the precipitate was collected by centrifugation andfiltration. The resulting solid was washed with water (52.00 L, 4volumes), then dried in a vacuum oven held at 35-45° C. for 12 hourswhereupon Karl Fischer analysis indicated that the water content wasless than 1.0%. The solid material was collected, amounting to 8.89 kgof the product (75.68% yield, 97.1% purity) as an off-white solid.

Alternative Process to G-2-a

To ethyl5-bromo-4-methyl-2-[3-(1-methyl-1-tert-butoxycarbonylethyl)ureido]-3-thenoate(0.65 kg, 1.0 eq.) was charged 1,4-dioxane (20.3 kg, 30 v/w). Theresulting slurry is then analyzed by KF and water is added such that KFis between about 0.1% and about 0.4%. Potassium tert-butoxide (0.85 kg,5.0 eq.) was then added and 1,4-dioxane (0.52 kg, 0.8 w/w) was added towash down the hopper. The mixture was heated to about 47° C. untildeemed complete, and then cooled to between about 10° C. and about 20°C., at which point acetic acid (0.44 kg, 5 eq.) is slowly added suchthat the temperature remains within this range. Water (1.95 kg, 3 v/wt)is added and the aqueous layer cut. While keeping the pot temperature atbelow about 40° C., the reaction is then concentrated to about 11V, thenwater (12.8 kg, 19.7 w/w) is added at 35° C. over 3 hours. The isolationmixture is cooled to 15° C. over 2 hours and after a further stirring(>1 hr) the quenched mixture was filtered. The resulting cake was washedwith 1,4-Dioxane/demineralized water (1/2 (w/w) (2.62 w/w)), followed bywashing with demineralized water (0.5 w/w). The wet product is driedunder vacuum at 35° C.-45° C.

Step 4. Synthesis of2-(2-Bromo-3-methyl-4,6-dioxo-1-thia-5,7-diaza-5,7-dihydroinden-5-yl)-2-methylpropionicacid

Into a 300 L reactor under nitrogen was charged dichloromethane (176.70L, 10 volumes), followed by intermediate G-2-a (17.74 kg, 1.0 eq.).Trifluoroacetic acid (32.4 L, 2 volumes) was added dropwise at atemperature between 15-25° C., and the reaction was stirred at thistemperature for three hours, sampling periodically for analysis by IPCuntil the amount of starting material remaining was no more than 2.0%.The mixture was then cooled to between 0-10° C., and water (182.41 L, 10volumes) was added dropwise, maintaining the temperature between 0-10°C. The reaction mixture was stirred for two hours at this temperature,and then the solid formed was collected by centrifugation andfiltration. The solid was washed with dichloromethane (2.3 volumes), andwater (5 volumes), then dried in a vacuum oven held at 35-45° C. for 12hours, whereupon Karl Fischer analysis indicated that the water contentwas less than 0.5%. The solid material was collected, amounting to 13.2kg of the product (86.7% yield, 98.1% purity) as an off-white solid.

Step 5. Synthesis of Benzyl2-(2-bromo-3-methyl-4,6-dioxo-1-thia-5,7-diaza-5,7-dihydroinden-5-yl)-2-methylpropionate(G-2-b)

Into a 300 L reactor under nitrogen was charged dichloromethane (116.7L, 10 volumes), followed by2-(2-Bromo-3-methyl-4,6-dioxo-1-thia-5,7-diaza-5,7-dihydroinden-5-yl)-2-methylpropionicacid (11.50 kg, 1.0 eq.). Carbonyldiimidazole (CDI, 6.51 kg, 1.2 eq.)was added batchwise to the reactor, maintaining the temperature of themixture below 25° C. The reaction mixture was stirred for three hours ata temperature between 20-30° C., sampling hourly, quenching withmethanol, for analysis by IPC until the amount of starting materialremaining was determined to be no more than 3.0%. Benzyl alcohol (4.64kg, 1.3 eq.) was then charged slowly into the reactor, keeping thetemperature below 25° C. The mixture was stirred for two hours at thistemperature, sampling hourly, quenching with methanol, for analysis byIPC until the amount of the intermediate was no more than 2.0%. Water (3volumes) was added to the mixture, which was stirred for 30 minutes,whereupon the phases were allowed to separate, and the organic phase wascollected, washed first with 1% HCl (3 volumes), then 2% sodiumbicarbonate (3 volumes), and finally water (3 volumes). The organicphase was concentrated under vacuum at a temperature below 50° C. untilthe remaining residue was not more than 4 volumes. MTBE (4 volumes) wasadded to the reactor, and the mixture was again concentrated undervacuum below 50° C. until the remaining residue was not more than 4volumes. MTBE (4 volumes) was again added to the reactor and the mixtureconcentrated under vacuum until the remaining residue was not more than4 volumes. One volume of MTBE was added to the reactor, and the mixturewas stirred for over five hours at a temperature between 5-15° C. Thesolid formed was centrifuged and collected by filtration. Into a 300 Lreactor was charged purified water (86.25 L, 7.5 volumes) andacetonitrile (28.75 L, 2.5 volumes), followed by the solid isolated inthe previous step. The mixture was stirred for 2-3 hours at atemperature between 15-25° C., then centrifuged, and the resulting solidcollected by filtration. The solid was dried in a vacuum oven for 12hours at a temperature between 35-45° C. The crude product (9.83 kg,67.8% yield, 97.7% purity) was isolated as an off-white solid. Thisproduct, plus that produced in a separate run (1.55 kg) were purifiedtogether by stirring for 16 hours in a mixture of acetonitrile (20 L),and purified water (60 L) in a 200 L drum at 25° C. The solids werecentrifuged, collected by filtration, and dried in a vacuum oven at35-45° C. for 12 hours. The total overall yield of G-2-b was 11.18 kg(67.2% yield, 98.9% purity) as an off-white solid.

Step 6. Synthesis of Benzyl2-{7-[(R)-2-(o-methoxyphenyl)-2-(tetrahydro-2H-pyran-4-yloxy)ethyl]-2-bromo-3-methyl-4,6-dioxo-1-thia-5,7-diaza-5,7-dihydroinden-5-yl}-2-methylpropionate(G-3-b)

Cesium carbonate (3369 g) was dried in a vacuum oven for 60 hours at50-60° C. Into a 100 L glass reactor under nitrogen was added the driedcesium carbonate (3340 g) in one portion, along with 9.2 L of NMP. Intoa 72 L glass reactor was charged NMP (15 L), (R)-G-1-a (3179 g), andG-2-b (3054 g), and the mixture was stirred until complete dissolutionwas observed. The solution in the 72 L reactor was transferred to the100 L reactor, using additional NMP (6.1 L) to rinse the residualcontents of the 72 L reactor into the 100 L reactor. The mixture in the100 L reactor was then heated to 100° C., and stirred at thattemperature for at least 60 hours, after which the amount of G-2-bremaining was 10.6% by HPLC. The temperature was decreased to between45-55° C. and purified water (23 L) was added, and the entire mixturetransferred to a 200 L glass reactor. Additional purified water (10 L),and methyl tert-butyl ether (MTBE, 31 L) were added, and the mixture wasstirred for 15 minutes. The phases were separated, and the organic phasewas washed with purified water (31 L). The aqueous phase was returned tothe reactor, and washed with MTBE (31 L), and stirred for 15 minutes.The combined organic layers were washed with brine (two portions of 15L) and transferred to a 100 L reactor. The organic mixture wasconcentrated under vacuum at 70° C. to a volume of 15 L. Ethanol (31 L)was added and the mixture was concentrated under vacuum at 70° C. to avolume of 21 L, and the ethanol addition and concentration was repeatedone more times. The mixture was heated to between 70-80° C. and stirreduntil complete dissolution was observed. The temperature was decreasedto between 45-55° C. over four hours, and held at that temperature forfive hours. The temperature was then decreased to between 15-25° C. overat least three hours, and held at that temperature for three hours. Thesolids formed were vacuum filtered, and rinsed with ethanol (6.1 L). Theresulting solids were dried in a vacuum oven at between 35-45° C. for 28hours, affording G-3-b (2993 g, 64% yield).

Step 7. Synthesis of G-4-b

Into a 72 L glass reactor under nitrogen with stirring were charged THF(37 L) and oxazole (918 g), and the temperature was decreased to between−80 and −60° C. 2.5 Molar n-butyllithium in hexanes (3.98 kg, stored atroom temperature) was added to the reactor, maintaining the temperatureof the reaction below −60° C. The mixture was stirred at thistemperature for 90 minutes. Zinc (II) chloride (5059 g) was added ineight portions, maintaining the temperature of the mixture below −60°C., and the mixture was stirred at that temperature for one hour beforewarming to 10-20° C. by removing the cooling bath. The contents of the72 L reactor were transferred to a 100 L glass reactor under nitrogen,using THF (4145 mL) to rinse the residue from the 72 L reactor into the100 L reactor. The mixture was stirred, and the temperature was adjustedto between 10-20° C. Intermediate G-4-b (4192 g, 1.0 eq.) was added tothe reactor followed by Pd(PPh₃)₄ (357 g), and the temperature wasadjusted to between 55-65° C., and the mixture was stirred at thattemperature for 12 hours, whereupon the amount of G-4-b remaining wasdetermined by HPLC to be no more than 0.07%. The temperature wasdecreased to between 15-25° C., and the mixture was transferred to a 200L reactor together with methyl tert-butyl ether (MTBE, 41 L) andpurified water (21 L). The mixture was stirred for 18 minutes, and thephases were separated. The organic phase was stirred with MTBE (41 L)and saturated ammonium chloride (41 L), the phases separated, and theorganic phase washed again with saturated ammonium chloride (21 L),followed by 2N HCl (21 L), and twice with purified water (21 L each).The organic layer was transferred to a 100 L reactor and concentratedunder vacuum at 70° C. to a volume of 41 L. The mixture was cooled tobetween 15-25° C., and transferred to a 75 L reactor and treated withactivated charcoal (Darco G 60, 829 g), and stirred for at least 15hours. The mixture was filtered through diatomaceous earth (Celite, 2520g) slurried in MTBE (13 L), rinsing the reactor with MTBE (21 L). Thefiltrate was concentrated under vacuum at 70° C. to a volume of 29 L,then twice diluted with ethanol (41 L), and concentrated to a volume of29 L. The temperature was increased to 79° C. whereupon completedissolution was observed. The temperature was then lowered to between45-55° C. over five hours, and held at that temperature for nine hours.The temperature was lowered to between 15-25° C. over at least 3 hours,and the solid formed was collected by filtration, using two portions ofethanol (4150 mL each) to rinse the contents of the reactor into thefilter and wash the filter cake. The collected solids were dried in avacuum oven at 45° C. for 18 hours, affording crude G-4-b (3463 g). Thecrude product was charged to a 100 L reactor containing ethanol (28 L),and purified water (7 L), and the mixture was heated to 70° C. withstirring, whereupon complete dissolution was observed. The mixture wascooled to 45° C. over 4.5 hours and held at that temperature for sixhours. The mixture was then cooled to 20° C. over five hours, and heldat that temperature for three hours, and the solids formed werecollected by filtration, washing the contents of the reactor into thefilter with ethanol (2770 mL) and purified water (693 mL). The purifiedsolid was dried in a vacuum oven at 45° C. for 20 hours, resulting inpurified G-4-b (4116 g, 75% yield).

Step 8. Synthesis of Compound 1 from G-4-b

Into a 20 L autoclave were charged THF (15 L) and G-4-b (1503 g, 1.0eq.). 10% palladium on carbon (76 g, dry basis) was added, and theautoclave was purged three times, backfilling with 15 p.s.i. nitrogeneach time, then purged five times, backfilling with 19 p.s.i. hydrogengas each time. The mixture was stirred under 19 p.s.i. hydrogen forseven hours, and the autoclave was purged and backfilled with nitrogen.The mixture was filtered through diatomaceous earth (Celite, 1247 g)slurried in THF (6 L), and the autoclave was rinsed into the filter withan additional 3.8 L of THF. A second batch was processed in the samemanner using 1538 g of G-4-b, and the filtrates from both batches werecombined and transferred to a 100 L glass reactor. Si-Thiol (Silicycle,757 g) was added to the reactor, and the temperature was adjusted tobetween 35-45° C. and stirred at that temperature for 15 hours. Thetemperature was then adjusted to between 15-25° C. and the mixture wasfiltered through diatomaceous earth (Celite, 1091 g), slurried in 8 L ofTHF. The reactor was washed into the filter with additional THF (15 L).The combined filtrates were concentrated to dryness under vacuum at atemperature between 35-40° C. MTBE (30 L) was added to dissolve theresidue, followed by purified water (30 L), and the mixture was adjustedto pH 13 with 2N aqueous sodium hydroxide (2.8 L), and stirred for 15minutes. The layers were separated and the aqueous phase was adjusted topH 1 with 2N HCl (3.5 L). The aqueous mixture was extracted with twoportions of dichloromethane (30 L each) and the combined organicextracts were washed with purified water (3.8 L). The organic layer wasconcentrated under vacuum at between 35-40° C., providing crude Compound1 (3614 g). The crude product was combined with acetonitrile (18 L) andheated to 75-85° C. with stirring until complete dissolution wasobserved. Purified water (18 L) was added, and the mixture was againheated to 75-85° C. The temperature was then decreased to 15-25° C. overone hour. The solids formed with collected by filtration and the filtercake washed with acetonitrile (3614 g) and purified water (3614 g). Thecollected solids were dried in a vacuum oven at 35° C. for 21 hours,affording Compound 1 of intermediate purity (2220 g). This material wassuspended in ethanol (15.5 L) and purified water (6.7 L), and heatedwith stirring to 76° C. until complete dissolution was observed. Thetemperature was decreased to 50° C. over four hours, and held at thattemperature for an additional three hours. The temperature was decreasedto 20° C. over three hours, then held at that temperature for anadditional six hours. The solids formed were collected by filtration,and the filter cake was washed with ethanol (2664 mL) and purified water(1.8 L). The solids were dried in a vacuum oven at 45° C. for 26 hours,affording 1895 g (71% yield) of pure Compound 1.

Example 36 Synthesis of Compound 1—Route B

Step 1. Synthesis of tert-Butyl2-methyl-2-[3-methyl-2-(1,3-oxazol-2-yl)-4,6-dioxo-1-thia-5,7-diaza-5,7-dihydroinden-5-yl]propionate(G-9-a)

Into a glass reactor under nitrogen were charged THF (10 volumes, 0.01%water by Karl Fischer), and oxazole (380.6 g, 4.0 eq., 0.05% water byKarl Fischer). The mixture was cooled to between −70 and −80° C., andn-butyllithium (2.5 M in hexanes, 2.65 L, 4.8 eq.) was added such thatthe temperature was maintained between −70 and −80° C., and the mixturewas stirred for an additional hour at that temperature. Zinc (II)chloride (1500 g, 8.0 eq.) was added in batches, such that thetemperature was maintained between −70 and −80° C. The mixture was thenwarmed to between 15-25° C., and the mixture was stirred for anadditional two hours at that temperature. Pd(PPh₃)₄ (79.5 g, 0.05 eq.)and G-2-a (556.5 g, 1.0 eq.) were added, and the mixture was heated to60° C. and stirred for 27 hours at that temperature. Once it wasdetermined that less than 5.0% of G-2-a remained by HPLC, the reactionwas cooled to between 30-40° C. and filtered. The filter cake was washedwith THF (two volumes), and the combined filtrates were combined andconcentrated under vacuum. Saturated aqueous ammonium chloride (10volumes), and methanol (10 volumes) were added to the residue, and thismixture was stirred for one hour, then filtered. The filter cake wasslurried with methanol (5 volumes), and purified water (1 volume), andstirred for 2 hours. The solids were collected by filtration, and driedin a vacuum oven at 35-45° C. to constant weight. The dried solids wereslurried in 1N HCl (15-20 volumes) for 24 hours, and the solids wereagain collected by filtration and the filter cake washed with purifiedwater until the pH of the filtrate reached pH 7. The collected solidswere dried in a vacuum oven at 35-45° C. to constant weight. The driedsolids were slurried in acetonitrile (8 volumes) at 80° C. for 30minutes, then the mixture was cooled to between 20-30° C. and stirredfor 3 hours. The resulting solids were collected by filtration andwashed with acetonitrile (2 volumes), then dried in a vacuum oven at35-45° C. to constant weight affording pure G-9-a.

Alternative Synthesis 2 of G-9-a

To a reactor was combined THF (482 mL, 6.9 v/w G-2-a) and oxazole (36.08g, 0.51 w/w G-2-a, 3 equiv.). The contents were cooled to about −20° C.and 2M isopropylmagnesium chloride in THF (304.8 g, 4.4 w/w G-2-a, 3.6equiv.) was charged dropwise maintaining the reaction contents at notmore than about −10° C. Once the addition was complete the reactor wascooled once more to about −15° C. and THF (35.1 g, 0.5 w/w G-2-a) wasused to rinse the Grignard solution forward. The solution was cooled toabout −20° C. and zinc chloride (141.8 g, 2 w/w G-2-a, 6 equiv.) wascharged portionwise while maintaining the reaction contents at not morethan about −10° C. Once the addition was complete the reaction contentswere warmed to about 22° C. over about one hour. To the reaction wascharged G-2-a (70.0 g) and THF (35.4 g, 0.5 w/w G-2-a) was used to rinsethe material into the reactor. The contents of the reactor were adjustedto about 60° C. and a slurry of palladium tetrakistriphenyphosphine(10.05 g, 0.14 w/w G-2-a, 0.05 equiv.) in THF (142 mL, 2 v/w G-2-a) wascharged. The slurry was rinsed forward with THF (39.4 mL, 0.5 v/w G-2-a)and the contents increased to about 65° C. for about 6 hours. Thecontents of the reactor were adjusted to about 20° C. and a solution ofacetic acid (38.8 g, 0.55 w/w G-2-a, 3.7 equiv.) in2-methyltetrahydrofuran (662 mL, 9.5 v/w G-2-a) was charged over notless than about three hours. The reaction contents were thenconcentrated under vacuum to about 14V before being filtered. Thereactor was charged with water (525 mL, 7.5 v/w G-2-a) which was thentransferred to the filter and used to slurry the filter cake. The slurrywas filtered and the resulting cake was washed successively with waterto remove salts. The solids were then removed from the filter andcombined with acetonitrile (1046 mL, 15 v/w G-2-a) in a reactor. Thereactor contents were heated to reflux for about 2 hours then cooled toabout 0° C. over about four hours and held at about 0° C. The slurry wasfiltered. The filter cake was washed with two portions of acetonitrile(2×143 mL, 2 v/w G-2-a) and then dried to afford G-9-a. ¹H NMR (400 MHz,CDCl₃): δ 12.31 (s, 1H), 8.20 (s, 1H), 7.36 (s, 1H), 2.73 (s, 3H), 1.64(s, 6H), 1.37 (s, 9H).

In some embodiments, the process above can be carried out wherein thepalladium catalyst can be added as a dry solid directly to the reactionmixture.

Alternative Synthesis 3 of G-9-a

To a reactor was combined THF (395 mL, 7.9 v/w G-2-a) and oxazole (25.6g, 0.51 w/w G-2-a, 3 equiv.). The contents were cooled to about −20° C.and 2M isopropylmagnesium chloride in THF (191.4 g, 3.9 w/w G-2-a, 3.2equiv.) was charged dropwise maintaining the reaction contents at notmore than about −10° C. Once the addition was complete the reactor wascooled once more to about −15° C. and a pre-made solution of zincchloride (102.0 g, 2 w/w G-2-a, 6 equiv.) in 2-methyltetrahydrofuran(349 mL, 7 v/w) was charged maintaining the reaction contents at notmore than about −10° C. Once the addition was complete, THF (22.07 g,0.45 w/w G-2-a) was charged and the reaction contents were warmed toabout 22° C. over about one hour. To the reaction was charged G-2-a(50.05 g) and THF (22.1 g, 0.45 w/w G-2-a) was used to rinse thematerial into the reactor. The contents of the reactor were adjusted toabout 45° C. and palladium tetrakistriphenyphosphine (10.05 g, 0.14 w/wG-2-a, 0.05 equiv.) was charged. The reactor contents were heated toabout 65° C. for about 6 hours. The contents of the reactor wereadjusted to about 20° C. and the reaction mixture was filtered, rinsingforward twice with THF (2×113 mL, 2.26 v/w G-2-a). To the filtrate in areactor was charged acetic acid (27.6 g, 0.55 w/w G-2-a, 3.7 equiv) overnot less than about three hours. The contents were aged about 8 hours at22° C. before concentrating to about 6 volumes. The reactor was chargedwith methanol (249 mL, 5 v/w G-2-a) over not less than about threehours. The reactor contents were then aged for about 12 hours at 20° C.before cooling to about −15° C. over about six hours and held at about−15° C. The slurry was filtered. The filter cake was washed with twoportions of methanol (2×101 mL, 2 v/w G-2-a), one portion ofacetonitrile (100 mL, 2 v/w G-2-a), and then dried to afford G-9-a. ¹HNMR (400 MHz, CDCl₃): δ 12.31 (s, 1H), 8.20 (s, 1H), 7.36 (s, 1H), 2.73(s, 3H), 1.64 (s, 6H), 1.37 (s, 9H).

Alternative Synthesis 4 of G-9-a

To a reactor was charged THF (80.5 mL, 8 v/w G-2-a), oxazole (5.18 g,0.51 w/w G-2-a, 3 equiv.) and lithium chloride (3.80 g, 0.38 w/w G-2-a,3.6 equiv). The contents were cooled to about −20° C. and 2Misopropylmagnesium chloride in THF (43.1 g, 4.31 w/w G-2-a, 3.6 equiv.)was charged dropwise maintaining the reaction contents at not more thanabout −10° C. Once the addition was complete, the reactor was cooledonce more to about −20° C. and 1.9 mol/L zinc chloride (78 mL, 7.8 w/wG-2-a, 6 equiv.) was charged maintaining the reaction contents at notmore than about −10° C. Once the addition was complete, the reactioncontents were warmed to about 22° C. over about 30 minutes and aged forabout 45 minutes. To the reaction was charged G-2-a (9.94 g) and thecontents of the reactor were adjusted to about 45° C.Tetrakis(triphenylphosphine)palladium(O) (1.39 g, 0.14 w/w G-2-a, 0.05equiv.) and THF (9.67 mL, 1 v/w G-2-a) were then charged. The contentswere adjusted to about 65° C. for about 12 hours. The contents of thereactor were adjusted to about 20° C. and a solution of acetic acid(5.52 g, 0.55 w/w G-2-a, 3.7 equiv.) in 2-methyltetrahydrofuran (17.5mL, 1.7 v/w G-2-a) was charged over not less than about three hours andaged. The reaction contents were then concentrated under vacuum to about14V. The slurry was warmed to about 45° C. for about 1 hour, cooled toabout 20° C. over about 2 hours, aged at about 20° C. and cooled toabout 0° C. over about 4 hours and aged. The slurry was filtered atabout 0° C. and the filter cake returned to the reactor. Water (149.92mL, 15 v/w G-2-a) was then charged and the slurry was agitated for about1 hour at about 20° C. before filtration. The filter cake was washedtwice with water before drying at about 40° C. under vacuum. The drysolids were charged to a reactor with acetonitrile (149 mL, 15 v/wG-2-a) and heated to reflux (about 77 to 80° C.) for about 2 hours, thencooled to 0° C. over about 4 hours and aged about 1 hour beforefiltration. The filter cake was washed twice with acetonitrile beforedrying at about 40° C. under vacuum to yield G-9-a. ¹H NMR (400 MHz,DMSO-d₆): δ 12.31 (s, 1H), 8.20 (s, 1H), 7.36 (s, 1H), 2.73 (s, 3H),1.64 (s, 6H), 1.37 (s, 9H).

Alternative Synthesis 5 of G-9-a

Oxazole (1.76 g, 0.51 w/w G-2-a, 2 equiv.) and THF (12.5 mL, 2.5 v/wG-2-a) were charged to a reactor and the contents cooled to about 0° C.TMPZnCl.LiCl (33 mL, 6.6 v/w G-2-a, 2.4 equiv.) was charged such thatthe internal temperature was about <5° C. In a separate reactor, G-2-a(5.03 g) and THF (40.0 mL, 8 v/w G-2-a) were charged to a reactor andcooled to about 0° C. TMPZnCl.LiCl (16 mL, 3.2 v/w G-2-a, 1.2 equiv.)was charged such that the internal temperature was about <5° C. Thesolutions were aged at about 0° C. for about 1 hour before warming toabout 20° C. and aging at that temperature. The solution of G-2-a wastransferred to the oxazole solution. ZnCl₂ (6.80 g, 1.36 w/w G-2-a, 4equiv.) was charged to the reaction mixture and the contents adjusted toreflux (about 65 to 70° C.). t-BuXPhos Pd G3 precatalyst (0.40 g, 0.08w/w G-2-a, 0.04 equiv.) was then added as a slurry in THF (10.0 mL, 2mL/g). The reaction mixture was stirred at reflux for about 60 minutes.The reaction mixture was cooled to about 20° C. and distilled to about10V pot volume under vacuum. The concentrated reaction mixture wasslowly quenched into an aqueous HCl solution (125 mL, 1N HCl, 25 v/wG-2-a) and agitated for about 17 hours. The slurry was filtered and thecake neutralized by washing three times with water (about 50 mL eachwash, 5 v/w G-2-a). The filter cake was dried at about 40° C. undervacuum. The dry solids were charged to a reactor with acetonitrile (75.0mL, 15 v/w G-2-a) and heated to reflux (about 77 to 80° C.) for about 90minutes, then cooled to about 20° C. over about 4 hours and aged about17 hours before filtration. The filter cake was washed twice withacetonitrile (about 10 mL each wash, 2 v/w G-2-a) before drying at about40° C. under vacuum to yield G-9-a. ¹H NMR (400 MHz, DMSO-d₆): δ 12.31(s, 1H), 8.20 (s, 1H), 7.36 (s, 1H), 2.73 (s, 3H), 1.64 (s, 6H), 1.37(s, 9H).

Alternative Synthesis 6 of G-9-a

Oxazole (3.38 g, 0.51 w/w G-2-a, 3 equiv.) was charged to a reactorcontaining THF (40.0 mL, 6 v/w G-2-a) and the contents were cooled toabout −15° C. A freshly prepared solution of TMPMgCl.LiCl (68 mL, 10.5w/w G-2-a, 0.85 mol/L, 3.6 equiv.) was charged such that the internaltemperature was less than about −10° C. The temperature was adjusted toabout −20° C., and a freshly prepared solution of ZnCl₂ in2-methyltetrahydrofuran (51 mL, 7.8 v/w G-2-a, 1.9 mol/L, 6.0 equiv.)was charged such that the internal temperature was less than about −10°C. The reaction mixture was warmed to about 20° C. over about 30 minutesand aged. G-2-a (6.47 g) was charged and the reaction mixture warmed toabout 45° C.

Tetrakis(triphenylphosphine)-palladium (O) (0.92 g, 0.14 w/w G-2-a, 0.05equiv) was then charged and rinsed forward with THF (6.3 mL, 1 v/wG-2-a). The temperature was adjusted to about 65° C. and stirred forabout 20 hours. The temperature was then adjusted to about 20° C. and afreshly prepared solution of acetic acid (3.56 g, 0.55 w/w G-2-a, 3.7equiv.) in 2-methyltetrahydrofuran (11.0 mL, 1.7 v/w G-2-a) was addedover about 3 hours. The slurry was aged an additional about 4 hoursbefore distilling to about 14V pot volume under vacuum. The slurry waswarmed to about 45° C. for about 1 hour, cooled to about 20° C. overabout 2 hours, aged at about 20° C. for about 6 hours and cooled toabout 0° C. over about 4 hours and aged for about 8 hours. The slurrywas filtered at about 0° C. and the filter cake returned to the reactor.Water (97.52 g, 15 v/w G-2-a) was then charged and the slurry wasagitated for about 4 hours at about 20° C. before filtration. The filtercake was washed twice with water (about 13 mL each wash, 2 v/w G-2-a)before drying to yield G-9-a. ¹H NMR (400 MHz, DMSO-d₆): δ 12.31 (s,1H), 8.20 (s, 1H), 7.36 (s, 1H), 2.73 (s, 3H), 1.64 (s, 6H), 1.37 (s,9H).

Step 2. Synthesis of tert-Butyl2-{7-[(R)-2-(o-methoxyphenyl)-2-(tetrahydro-2H-pyran-4-yloxy)ethyl]-3-methyl-2-(1,3-oxazol-2-yl)-4,6-dioxo-1-thia-5,7-diaza-5,7-dihydroinden-5-yl}-2-methylpropionate(G-4-a)

Into a glass reactor under nitrogen were charged G-9-a (150.0 g, 1.0eq.) and NMP (3 volumes), followed by G-1-a (1.10 eq.) and potassiumcarbonate (1.05 eq.). The mixture was heated to 130° C. and stirred atthat temperature for 16 hours. Once it was determined that less than4.6% of G-9-a remained by HPLC, the reaction was cooled to between25-35° C., and purified water was added (20 volumes) and stirred for 2hours. The solids formed were collected by filtration, and the filtercake was washed with purified water (5 volumes), then dried under vacuumat room temperature. The crude product was slurried in methanol (8volumes) and the mixture was heated to reflux, then cooled to between15-25° C. The solids formed were collected by filtration, affordingpurified G-4-a (170.7 g, 71.2% yield) as an off-white solid.

Alternative Synthesis of G-4-a

The stock solution of (R)-G-6-a stock solution (as prepared according toAlternative Synthesis of (R)-G-1-a discussed above) (89.34 g solution,21.67% (R)-G-1-a wt %, 1.2 equiv.) was charged to a reactor containingG-9-a (20.00 g, 1.0 equiv.), followed by a NMP rinse forward (3.0 g,0.15 v/w G-9-a) and addition of potassium carbonate (7.4 g, 0.37 w/wG-9-a, 1.05 equiv.). The contents were heated to about 115° C. andstirred for a minimum of about 22 hours until the reaction was deemedcomplete. The contents were cooled to about 30° C., and then slowlyadded into drinking water (200.0 g, 10 v/w G-9-a). Dichloromethane(211.6 g, 8 v/w G-9-a) was then added, and the solution was agitated forabout 30 minutes at about 22° C. Agitation was stopped and the solutionwas allowed to settle. The bottom organic layer was collected and thetop aqueous layer was extracted with dichloromethane (211.6 g, 8 v/wG-9-a) at about 22° C. for about 30 minutes. Agitation was again stoppedand the solution was allowed to settle. The top aqueous layer wasremoved and the bottom organic layer was combined with another organiclayer. The combined organic layers were distilled under vacuum tobetween about 3V and about 4V pot volume. Methanol (130.0 g, 8 v/wG-9-a) was added and the solution was distilled down to between about 3Vand about 4V pot volume. Methanol (79.6 g, 5 v/w G-9-a) was added andthe slurry was heated to reflux (about 63 to 69° C.) for about 2 hours.The slurry was then cooled to about 0° C. and filtered. The filter cakewas washed with methanol (31.60 g, 2 v/w G-9-a) at about 0° C. and driedto afford G-4-a. ¹H NMR (400 MHz, CDCl₃): δ 7.70 (d, J=0.4 Hz, 1H), 7.58(dd, J=1.6 Hz, J=7.6 Hz, 1H), 7.29 (td, J=1.6 Hz, J=8.0 Hz, 1H), 7.21(d, J=0.8 Hz, 1H), 7.03 (t, J=7.2 Hz, 1H), 6.86 (d, J=8.0 Hz, 1H), 5.39(dd, J=4.4 Hz, J=8.8 Hz, 1H), 4.18-4.15 (m, 1H), 3.99 (br, 1H), 3.86 (s,3H), 3.78-3.73 (m, 1H), 3.70-3.65 (m, 1H), 3.46-3.40 (m, 1H), 3.36-3.30(m, 2H), 2.86 (s, 3H), 1.80 (s, 3H), 1.76 (s, 3H), 1.76-1.71 (m, 2H),1.59-1.51 (m, 1H), 1.46 (s, 9H) 1.46-1.37 (m, 1H).

Step 3. Synthesis of Compound 1

Into a glass reactor under nitrogen were charged 9 M aq. H₂SO₄ (5volumes) and isopropyl alcohol (5 volumes), and the mixture was cooledto between 5-10° C. G-4-a (150.0 g, 1.0 eq.) was added such that thetemperature of the mixture was maintained between 5-10° C., and thereaction was stirred at that temperature for 20 hours. Once it wasdetermined that no more than 0.3% of starting G-4-a remained by HPLC,the mixture was poured into purified water (20 volumes) dropwise andstirred for one hour. The solids formed were collected by filtration,and the filter cake was washed with purified water (5 volumes). The cakewas resuspended in purified water (10 volumes) and the pH was adjustedto 8-9 with aqueous sodium hydroxide (20% w/w). The aqueous solution wasextracted with ethyl acetate (three portions of 5 volumes), and theaqueous layer was acidified to pH 4-5 with 4 M HCl. The aqueous solutionwas extracted with ethyl acetate (three portions of 10 volumes), and thecombined organic extracts were filtered, and concentrated under vacuumto dryness. The residue was dissolved in ethanol/water (7:3, 10 volumes)at between 70-80° C., and the resulting solution was cooled to 50° C.over 4 hours and held at that temperature overnight. The solution wasthen cooled to 20° C. over 3 hours, and held at that temperature for atleast three hours. The resulting solids were collected by filtration,and the filter cake was washed with ethanol/water (7:3, 2 volumes), thendried under vacuum to constant weight, affording purified Compound 1(110.0 g, 80.5% yield, >99% purity by HPLC, NMR).

Alternative Synthesis of Compound 1

A sulfuric acid solution was prepared by addition of concentratedsulfuric acid (47 g, 4.7 w/w G-4-a) to water (12 g, 1.2 v/w G-4-a)followed by a water (15 g, 1.5 v/w G-4-a) rinse forward. 2-Propanol (37g, 4.7 v/w G-4-a) was slowly charged to a reactor containing sulfuricacid solution at about 9° C. while maintaining the reaction contents atno more than about 40° C., and the solution was cooled to about 5° C.G-4-a (10 g, 1.0 eq.) was charged to the solution, followed by a2-propanol rinse forward (2 g, 0.25 v/w G-4-a). The contents were cooledto about 7° C. and stirred for a minimum of about 21 hours. The contentswere slowly added into water, and the slurry was agitated for about 30minutes. The slurry was filtered, and the filter cake was washed anddried under vacuum for about 4 hours. The crude wet cake was chargedback to the reactor, followed by additions of ethyl acetate (40 g, 4.4v/w G-4-a) and water (100 g, 10 v/w G-4-a). The slurry was adjusted topH at about 8-9 with an about 20 wt % sodium hydroxide solution at about22° C., and then agitated for about 30 minutes at about 22° C. Thesolution was allowed to settle. The top organic layer was collected andthe bottom aqueous layer was washed with ethyl acetate (40 g, 4.4 v/wG-4-a) at about 22° C. for about 30 minutes. The solution was allowed tosettle, and the top organic layer was removed. 2-Methyltetrahydrofuran(86 g, 10 v/w G-4-a) was then added, was adjusted to pH at about 4-5with an about 4 N HCl solution at about 22° C. The solution was agitatedfor about 30 minutes at about 22° C. and then allowed to settle. Thebottom aqueous layer was extracted with 2-methyltetrahydrofuran (52 g, 6v/w G-4-a) at about 22° C. for about 30 minutes. After the solution wasallowed to settle, the bottom aqueous layer was removed. The organiclayers were combined and distilled under vacuum (jacket at about ≤45°C.) to about 4V pot volume. Ethanol (55.4 g, 7 v/w G-4-a) was added andthe reaction as distilled (repeated twice). Ethanol was again added(23.7 g, 3 v/w G-4-a), followed by water (30 g, 3 v/w G-4-a). Thereaction was heated to about 75° C. and then cooled over about 4 hoursto about 50° C., then to about 0° C. over about 5 hours. The reaction isthen aged and filtered, and the cake is washed with a precooled mixtureof ethanol (9.5 g, 1.2 v/w G-4-a) and water (6 g, 0.6 v/w G-4-a). Theresulting filter cake was washed with dried to afford Compound 1. ¹H NMR(400 MHz, CDCl₃): δ 7.70 (s, 1H), 7.57 (dd, J=1.6 Hz, J=7.6 Hz, 1H),7.29 (td, J=1.6 Hz, J=8.0 Hz, 1H), 7.23 (d, J=0.4 Hz, 1H), 7.02 (t,J=7.6 Hz, 1H), 6.86 (d, J=8.4 Hz, 1H), 5.39 (dd, J=5.6 Hz, J=8.0 Hz,1H), 4.17-4.14 (m, 1H), 4.04 (br, 1H), 3.86 (s, 3H), 3.78-3.67 (m, 2H),3.46-3.40 (m, 1H), 3.37-3.32 (m, 2H), 2.85 (s, 3H), 1.87 (s, 3H), 1.83(s, 3H), 1.75-1.72 (m, 2H), 1.59-1.51 (m, 1H), 1.48-1.39 (m, 1H).

Example 37 Enzymatic Resolution Screen

A variety of lipase enzymes were assayed for their effectiveness in thekinetic resolution of racemic alcohols of formula rac-G-5, according tothe following procedure. Test substrate rac-G-5-a was dissolved ineither toluene or MTBE together with 1 equivalent of acyl donor (vinylacetate). 5-10 milligrams of the lipase to be tested was added, and themixture was stirred for 3-10 hours while being sampled periodically foranalysis by chiral HPLC. Table 10 below reports the results of theenzymatic resolution screen. ND means “not determined”.

TABLE 10 Results of enzymatic resolution screen % Substrate % Productremaining formed Selectivity (% AUC, 220 nm) Enzyme (28 h) (acetate; 28h) R-acetate S-acetate R-alcohol S-alcohol Lipase OF 59.9 40.1 16.5521.43 26.27 32.75 Acylase >95% <5% ND ND ND ND (Amano) Lipase PS30 >95%<5% ND ND ND ND CAL-B 21.4 78.6 48.87 30.25 0   20.26 Lipase PPL >95%<5% ND ND ND ND CAL-A 40.4 59.6 37.92 13.96  4.13 28.85 Lipase 58.9 41.1 9.74 30.51 40.92 18.18 Mucor Meihei

Example 38 Enzymatic Resolution Substrate Screen

The enzymatic resolution and hydrolysis of Example 37 was also performedon a wide range of alcohol substrates of formula rac-G-5 to demonstratethe scope of the transformation. Table 11 below reports the results ofthe substrate screen.

TABLE 11 Alcohol structures following acyl group % e.e. of hydrolysisalcohol

95-100

95-100

95-100

95-100

95-100

95-100

95-100

95-100

95-100

95-100

95-100

95-100

95-100

95-100

95-100

95-100

95-100

95-100

95-100

95-100

95-100

95-100

95-100

95-100

95-100

95-100

95-100

95-100

95-100

95-100

95-100

95-100

95-100

95-100

Example 39 Studies of Compound 1

Form I of Compound 1 was evaluated in three studies: Study A, Study B,and Study C.

Study A evaluated the safety and tolerability of 30, 80, 200, 500, 800,and 1000 mg in the fasted state and 200 mg following a high fat meal(fed state) to cohorts of 8 healthy subjects (6 active and 2 placebocontrol per group).

Study B (five (5) cohorts of 8 subjects (6 active and 2 placebo))evaluated 50 mg twice daily (BID) (100 mg daily), 100 mg once daily (QD)(100 mg daily), 100 mg BID (200 mg daily), 200 mg QD (200 mg daily), or150 mg QD (150 mg daily), or matching placebo. Subjects receivedmultiple oral doses of Compound 1 or placebo for 9 consecutive days,with a single oral dose of Compound 1 or placebo on the morning of Day10. Doses were administered approximately 30 minutes after meals.

Study C evaluated the effects on fractional de novo lipogenesis (DNL) ofa single oral dose of 20, 50, or 200 mg Compound 1 compared to placebo(3 cohorts of 10 subjects). DNL was assessed by measuring appearance ofde novo synthesis of palmitate in very-low density lipoproteins (VLDL)in response to oral fructose (30 minute intervals over 10 hours) using[¹³C]acetate and mass isotopomer distribution analysis (MIDA). The twodosing periods were separated by a minimum of 5 days for washout of the[¹³C]acetate and study medication.

Study A

Table 12 summarizes PK parameters (mean) under fasted conditions ofStudy A. The reported factors may vary up to about 2%.

The comparisons of plasma Compound 1 AUC_(t) and AUC_(∞) following 200mg Compound 1 under fed versus fasted conditions resulted in 90%confidence intervals with lower bounds outside the 80% to 125% referenceinterval, the geometric mean ratios (GMRs) demonstrated that overallplasma Compound 1 exposure was only approximately 9% to 14% lower underfed compared to fasted conditions, which may not be a clinicallyrelevant difference. The comparison of plasma Compound 1 C_(max)following 200 mg Compound 1 under fed versus fasted conditions indicatedmaximum plasma Compound 1 exposure was approximately 68% lower under fedcompared to fasted conditions. The plasma Compound 1 concentrationversus time profiles demonstrated a delay in the first quantifiableconcentration and a prolonged absorption/distribution phase observedunder fed compared to fasted conditions. However, the mean t_(1/2),CL/F, and Vz/F values and median t_(max) values were comparablefollowing 200 mg Compound administered under fed and fasted conditions.

TABLE 12 Mean (SD) Pharmacokinetic Parameters after a Single Dose ofOral Compound 1 to Healthy Volunteers PK 30 mg 80 mg 200 mg 500 mg 800mg 1000 mg Parameters (n = 6) (n = 6) (n = 6) (n = 6) (n = 6) (n = 6)t_(1/2) 4.5 ± 1.6   7 ± 2.8   12 ± 1.4 10.2 ± 2.1  8.2 ± 3.3  9.5 ± 2.6t_(max) (hr)^(a) 1.3 (0.23, 2.0) 1.8 (1.5, 2.0) 1.9 (1.0, 4.0) 1.9 (1.0,3.0) 2.1 (1.0, 3.0) 2.4 (1.0, 4.0) C_(max) (ng/mL) 80 ± 66 101 ± 48  416± 22 1112 ± 1149 2571 ± 1875  8375 ± 3207 AUC0-12 NC^(b) 395 ± 198 1005± 545 1244 ± 547  NC^(b) NC^(b) (h*ng/mL) AUC_(0-t) 176 ± 104 363 ± 2151209 ± 536 2931 ± 2438 6424 ± 3184 17419 ± 8403 (h*ng/mL) AUC_(∞) · 179± 115 402 ± 225 1254 ± 616 2963 ± 2458 6464 ± 3186 17509 ± 8413(h*ng/mL) % Metabolite/ 8.0% 6.6% 8.4% 5.9% 9.7% 5.6% Parent Ratio^(a)Mean (Min, Max) ^(b)NC—Not calculatedStudy B

Table 13 summarizes PK parameters of Study B after 10 days. The reportedfactors may vary up to about 2%.

Maximal exposure (C_(max)) of Compound 1 generally increased from Day 1to Day 10 and overall exposure (AUC_(t)) increased approximately 1.5-3.0fold on Day 10 compared to Day 1. Mean t_(1/2) was within a 2-fold rangeindependent of dose or regimen on each study day, and exhibited a trendfor longer mean half-life on Day 10 versus Day 1 except at the highestdose (200 mg QD).

TABLE 13 Pharmacokinetic Parameters after Multiple Dose of Compound 1 50mg BID 100 mg QD 100 mg BID 150 mg QD 200 mg QD (n = 6) (n = 6) (n = 6)(n = 6) (n = 6) PK Parameter Day 1 Day 10 Day 1 Day 10 Day 1 Day 10 Day1 Day 10 Day 1 Day 10 t_(1/2)  3.5 ± 1.6 10.3 ± 6.7  4.3 ± 0.7 7.9 ± 4.5   5.6^(a)  6.8 ± 1.6 3.9 ± 1.1 6.6 ± 2.8 5.9 ± 3.6 5.9 ± 1 t_(max)(hr)^(b c) 2.4 4.5 3.3, 4.5 5.2 5.2 3.3 6.5 4.7 3.7 (1.5, 3) (2,8) (1, 6) (2, 12) (3, 8) (2, 6) (1, 3) (1, 12) (2, 6) (1.5, 6) C_(max) 41 ± 14 49 ± 15 65 ± 32 54 ± 22 61.6 ± 15  121 ± 56 94 ± 40 111 ± 52 152 ± 68  198 ± 87 (ng/mL)^(d) AUC₀-₁₂ 143 ± 29 ND^(e) 234 ± 86  285 ±115 345 ± 78 ND^(e) 489 ± 218 637 ± 246 707 ± 191 1224 ± 362 (h*ng/mL)AUC_(0-t) 143 ± 29 403 ± 104 268 ± 96  400 ± 181 345 ± 77 1122 ± 362 572± 247 933 ± 424 868 ± 220 2051 ± 819 (h*ng/mL) AUC_(∞ ·) 178 ± 41 ND^(e)278 ± 110 ND^(e) 671^(a) ND^(e) 587 ± 254 ND^(e) 979 ± 286 ND^(e)(h*ng/mL) % Metabolite/ 6.4% 7.2% 4.2% 7.3% 6.3% 5.0% 8.3% 6.2% 6.4%5.2% Parent Ratio ^(a)Value available for one subject, therefore no STDcalculated ^(b)Tmax D10-steady state ^(c) Mean (Min, Max) ^(d)Cmax D10 -steady state ^(e)ND—Not doneStudy C

In Study C, mean Compound 1 plasma PK parameters are summarized asfollows: at a dose of 20 mg, t_(max) (hr)^(a)=1.8 (1, 3), C_(max)(ng/mL)=15.5+11.5, AUC_(t) (hr*mg/mL)=40.0+16.0, % Metabolite/ParentRatio=4.3%; at a dose of 50 mg, t_(max) (hr)^(a)=1.30 (0.99, 2), C_(max)(ng/mL)=36.5+17.0, AUC_(t) (hr*mg/mL)=98.8+41.3, % Metabolite/ParentRatio=11%; at a dose of 200 mg, t_(max) (hr)^(a)=2.0 (1.3), C_(max)(ng/mL)=222+196, AUC_(t) (hr*mg/mL)=518.±295, % Metabolite/ParentRatio=5.0%. ^(a) indicates Mean (Min, Max). The reported factors mayvary up to about 2%.

Example 40 Studies of Compound 1 in Subjects with Normal and ImpairedHepatic Function

This study evaluates Form I of Compound 1 in subjects with normal andimpaired hepatic function and to evaluate the safety and tolerability ofCompound 1 single-dose administration in subjects with normal andimpaired hepatic function.

The cohorts are as follows: Cohort 1 (Mild Hepatic Impairment) includesapproximately 20 subjects (10 per group (mildly impaired and matchedcontrols) for 8 evaluable per group); Cohort 2 (Moderate HepaticImpairment) includes approximately 20 subjects (10 per group (moderatelyimpaired and matched controls) for 8 evaluable per group); and Cohort 3(Severe Hepatic Impairment) includes approximately 20 subjects (10 pergroup (severely impaired and matched controls) for 8 evaluable pergroup)

Eligible subjects include male and non-pregnant/non-lactating femalesubjects, ages 18-70 years inclusive with mildly impaired, moderatelyimpaired, severely impaired, and normal hepatic function. Subjects willbe current non-smokers (no use of tobacco, nicotine-containing or THCcontaining products within the last 14 days). Each subject in thecontrol group will be matched for age (±10 years), gender, race, andbody mass index (±15% 18≤BMI≤36 kg/m²) with a subject in the hepaticimpairment group. A subject with normal hepatic function may serve as amatched control across cohorts but may only serve as a matched controlto one hepatic impaired subject within a cohort. Cohorts 1 and 2 may bedosed in parallel, with dosing for Cohort 3 (severe hepatic impairment)proceeding after review of safety and preliminary PK data (if available)from hepatically impaired subjects in the previous cohorts. Based on thecumulative review of safety and PK data from Cohorts 1 and 2, Cohort 3may or may not be initiated at the discretion of the investigator andSponsor. Dosing in subjects with normal hepatic function will beginafter a matched subject with hepatic impairment has completed all Day 1PK assessments (e.g., 96 hours postdose).

Eligible subjects may exhibit varying degrees of hepatic impairment andmatched healthy controls. Those subjects with hepatic impairment will becategorized based upon the CPT classification system for hepaticimpairment as recommended by the United States FDA and internationalguidance documents (U.S. Department of Health and Human Services Foodand Drug Administration Center for Drug Evaluation and Research (CDER);Center for Biologics Evaluation and Research (CBER) 2003). Within theChild-Pugh-Turcotte (CPT) system, subjects will be assigned to Class A,B, or C (CPT Class A, B, or C) based on a cumulative score evaluatingthe presence and severity of hyperbilirubinemia, hypoalbuminemia,prolongation of INR for coagulation time, ascites, and hepaticencephalopathy. Classification of hepatic impairment will be assigned asfollows: (1) Mild: Class A, CPT score of 5-6; (2) Moderate: Class B, CPTscore of 7-9; and (3) Severe: Class C, CPT score of 10-15.

Also, subjects with hepatic impairment and healthy matched controls maybe enrolled. The control group may consist of matched healthy subjectswith normal hepatic function.

Inclusion Criteria

Additional inclusion criteria may be used, for example:

-   -   Aside from hepatic insufficiency, the subject must, in the        opinion of the investigator, be sufficiently healthy for study        participation based upon medical history, physical examination,        vital signs, and screening laboratory evaluations    -   May have diagnosis of chronic (>6 months), stable hepatic        impairment with no clinically significant changes within 3        months (or 90 days) prior to study drug administration (Day 1)    -   May meet all of the following laboratory parameters at        Screening:        -   alanine aminotransferase (previously serum glutamic pyruvic            transaminase (ALT) value≤10×upper limit of normal (ULN)        -   aspartate aminotransferase (AST) value≤10×ULN        -   Absolute neutrophil count≥1,000/mm³        -   Platelets≥25,000/mm³        -   Hemoglobin≥8 g/dL        -   α-fetoprotein≤50 ng/mL    -   Subjects with mild hepatic impairment must have a score on the        Child Pugh Turcotte scale of 5-6 at Screening. If a subject's        score changes during the course of the study, the score at        Screening will be used for classification    -   Subjects with moderate hepatic impairment must have a score on        the Child Pugh Turcotte scale of 7-9 at Screening. If a        subject's score changes during the course of the study, the        score at Screening will be used for classification    -   Subjects with severe hepatic impairment must have a score on the        Child Pugh Turcotte scale of 10-15 at Screening. If a subject's        score changes during the course of the study, the score at        Screening will be used for classification.    -   Subjects with hepatic impairment with comorbid diseases not        associated with hepatic impairment requiring medication(s) must        be taking the medication(s) without a change in dose for at        least 4 weeks (or 5 half-lives, whichever is longer) prior to        Screening. Any change in the dosage during this timeframe should        be reviewed and approved by the Sponsor.        Dosing and Administration

On Day 1 subjects will receive a single oral dose of 20 mg Compound 1(2×10 mg capsule) orally. Dosing in subjects with normal hepaticfunction will begin after a matched subject with hepatic impairment hascompleted all Day 1 PK assessments (e.g., 96 hours postdose). Cohorts 1and 2 may be dosed in parallel, with dosing for Cohort 3 (severe hepaticimpairment) proceeding after review of safety and preliminary PK data(if available) from hepatic impaired subjects in the previous cohorts.Based on the cumulative review of safety and PK data from Cohorts 1 and2, Cohort 3 may or may not be initiated at the discretion of theinvestigator and Sponsor. Pharmacokinetic Assessments and otherAssessments (as discussed above) may be performed.

Example 41 Studies Compound 1 in Subjects with NASH

This study evaluates the safety, tolerability, and efficacy of Form I ofCompound 1 in subjects with NASH. To be eligible to participate,subjects may have hepatic steatosis and increased liver stiffness asassessed by Magnetic Resonance Imaging-Protein Density Fat Fraction(MRI-PDFF) and Magnetic Resonance Elastography (MRE), respectively, or ahistorical liver biopsy consistent with NASH and noncirrhotic fibrosis.Any subject with history of decompensated liver disease, includingascites, hepatic encephalopathy or variceal bleeding may be ineligible.

Subjects meeting the study's entry criteria will be randomly assigned ina 2:2:1 ratio to 1 of 3 different treatment groups, A, B, and C asdiscussed below. Randomization may be stratified by the presence orabsence of diabetes mellitus as determined by medical history, use ofmedication for indication of diabetes mellitus, or based on Screeninglab values if previously undiagnosed (i.e., hemoglobin A1c≥6.5% ORfasting plasma glucose≥126 mg/dL). Study drugs will be administered fora total of 12 weeks from the Baseline/Day 1 visit.

5 milligrams of Compound 1 or placebo, or 10 milligrams of Compound 1 orplacebo, may be administered with or without food once daily. Study drugdosing and administration may occur as follows based on treatment grouprandomization:

-   -   Treatment Group A: Compound 1 5 mg administered orally once        daily;    -   Treatment Group B: Compound 1 20 mg administered orally once        daily;    -   Treatment Group C: Placebo administered orally once daily.

Subjects may be evaluated during the studies at weeks 0, 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or24 weeks by the following:

-   -   QoL Questionnaires (Short Form (36) Health Survey (SF-36), World        Productivity and Activity Impairment (WPAI), and Chronic Liver        Disease questionnaire (CLDQ)). Note: It is recommended that QoL        questionnaires be completed prior to any study procedures being        performed and prior to the subject seeing a health care        provider.    -   Symptom driven physical examination    -   Record vital signs, waist circumference, and body weight    -   Obtain blood samples for Chemistry, Hematology, Coagulation        Panel, Lipid Profile, Hemoglobin A1c, Biomarkers, or Genomic        testing (only if the subject consented to participate in the        optional genomic research)    -   Conduct standard 12-Lead ECG    -   Perform FibroScan® (if available)    -   Collect urine samples for urine pregnancy test for females of        child bearing potential only or biomarkers    -   Collect stool sample for Biomarkers (see Study Reference Binder        for instructions)    -   Dispense study drugs, and provide subject with instruction on        appropriate dosing and administration; subject will take the        Baseline/Day 1 dose of study drugs on-site    -   Collect MRE data    -   Collect MRI-PDFF data    -   Record all concomitant medications that the subject has taken        since the previous visit    -   Record any serious adverse events and all adverse events        occurring since the Screening visit.

While we have described a number of embodiments of this invention, it isapparent that our basic examples may be altered to provide otherembodiments that utilize the compounds and methods of this invention.Therefore, it will be appreciated that the scope of this invention is tobe defined by the appended claims rather than by the specificembodiments that have been represented by way of example.

We claim:
 1. A crystalline form of Compound 1:

(Compound 1 Form I) characterized by an X-ray powder diffractogramcomprising the following peaks: 9.3, 15.0, and 19.8°2θ±0.2°2θ, asdetermined on a diffractometer using Cu—Kα radiation at a wavelength of1.54 Å.
 2. The crystalline form of claim 1, wherein the diffractogramcomprises one or more additional peaks at 16.0, 24.0, 25.8, and27.3°2θ±0.2°2θ.
 3. The crystalline form of claim 2, wherein thediffractogram comprises peaks at 16.0 and 25.8°2θ±0.2°2θ.
 4. Thecrystalline form of claim 1, characterized by a differential scanningcalorimetry (DSC) curve that comprises an endotherm between 189° C. to193° C.
 5. A pharmaceutical composition comprising the crystalline formof claim 3 and a pharmaceutically acceptable carrier, adjuvant ordiluent.
 6. A pharmaceutical composition comprising a therapeuticallyeffective amount of the crystalline form of Compound 1 according toclaim 1, and a pharmaceutically acceptable carrier, adjuvant or diluent.7. A method of inhibiting ACC in a patient in need thereof comprisingadministering to the patient the crystalline form of claim
 1. 8. Themethod according to claim 7, wherein the patient is suffering fromnon-alcoholic fatty liver disease.
 9. The method according to claim 8,wherein the non-alcoholic fatty liver disease is non-alcoholicsteatohepatitis.
 10. The method of claim 7, wherein the patient issuffering from acne vulgaris.